bims-axbals Biomed News
on Axonal biology and ALS
Issue of 2024–06–09
28 papers selected by
TJ Krzystek, ALS Therapy Development Institute
  1. Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.
  2. cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.
  3. TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.
  4. Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration.
  5. Hyperactivation of MEK1 in cortical glutamatergic neurons results in projection axon deficits and aberrant motor learning.
  6. Advances and challenges in modeling inherited peripheral neuropathies using iPSCs.
  7. The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations.
  8. DDAH-1 maintains endoplasmic reticulum-mitochondria contacts and protects dopaminergic neurons in Parkinson's disease.
  9. Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS.
  10. International network for ALS research and care (INARC).
  11. Rab6-mediated polarized transport of synaptic vesicle precursors is essential for the establishment of neuronal polarity and brain formation.
  12. TDP43 Interacts with MLH1 and MSH6 Proteins in A DNA Damage-Inducible Manner.
  13. The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.
  14. Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms.
  15. Molecular mechanisms defining penetrance of LRRK2-associated Parkinson's disease.
  16. Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.
  17. A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction.
  18. Capturing totipotency in human cells through spliceosomal repression.
  19. Spinal cord neurone loss and foot placement changes in a rat knock-in model of amyotrophic lateral sclerosis Type 8.
  20. Biphenotypic Cells and α-Synuclein Accumulation in Enteric Neurons of Leucine-Rich Repeat Kinase 2 Knockout Mice.
  21. Impaired cathepsin D in retinal pigment epithelium cells mediates Stargardt disease pathogenesis.
  22. TARDBP Mutations in Facial-Onset Sensory and Motor Neuronopathy.
  23. Coxsackievirus A10 impairs nail regeneration and induces onychomadesis by mimicking DKK1 to attenuate Wnt signaling.
  24. Differentiation of Enteric Nervous System Lineages from Human Pluripotent Stem Cells.
  25. A fluid-walled microfluidic platform for human neuron microcircuits and directed axotomy.
  26. ESCRT disruption provides evidence against trans-synaptic signaling via extracellular vesicles.
  27. Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.
  28. Cell-type-specific effects of age and sex on human cortical neurons.
  1. bioRxiv. 2024 May 26. pii: 2024.05.24.595817. [Epub ahead of print]
    Skeletal myotubes expressing ALS mutant SOD1 induce pathogenic changes, impair mitochondrial axonal transport, and trigger motoneuron death.
    Pablo Martínez, Mónica Silva, Sebastián Abarzúa, María Florencia Tevy, Enrique Jaimovich, Martha Constantine-Paton, Fernando J Bustos, Brigitte van Zundert.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the loss of motoneurons (MNs), and despite progress, there is no effective treatment. A large body of evidence shows that astrocytes expressing ALS-linked mutant proteins cause non-cell autonomous toxicity of MNs. Although MNs innervate muscle fibers and ALS is characterized by the early disruption of the neuromuscular junction (NMJ) and axon degeneration, there are controversies about whether muscle contributes to non-cell-autonomous toxicity to MNs. In this study, we generated primary skeletal myotubes from myoblasts derived from ALS mice expressing human mutant SOD1 G93A (termed hereafter mutSOD1). Characterization revealed that mutSOD1 skeletal myotubes display intrinsic phenotypic and functional differences compared to control myotubes generated from non-transgenic (NTg) littermates. Next, we analyzed whether ALS myotubes exert non-cell-autonomous toxicity to MNs. We report that conditioned media from mutSOD1 myotubes (mutSOD1-MCM), but not from control myotubes (NTg-MCM), induced robust death of primary MNs in mixed spinal cord cultures and compartmentalized microfluidic chambers. Our study further revealed that applying mutSOD1-MCM to the MN axonal side in microfluidic devices rapidly reduces mitochondrial axonal transport while increasing Ca2+ transients and reactive oxygen species (i.e., H 2 O 2 ). These results indicate that soluble factor(s) released by mutSOD1 myotubes cause MN axonopathy that leads to lethal pathogenic changes.
    DOI:  https://doi.org/10.1101/2024.05.24.595817
  2. Proc Natl Acad Sci U S A. 2024 Jun 11. 121(24): e2400732121
    cAMP/PKA signaling regulates TDP-43 aggregation and mislocalization.
    Diana M Ho, Muhammad Shaban, Faisal Mahmood, Payel Ganguly, Leonardo Todeschini, David Van Vactor, Spyros Artavanis-Tsakonas.
      Cytoplasmic mislocalization and aggregation of TDP-43 protein are hallmarks of amyotrophic lateral sclerosis (ALS) and are observed in the vast majority of both familial and sporadic cases. How these two interconnected processes are regulated on a molecular level, however, remains enigmatic. Genome-wide screens for modifiers of the ALS-associated genes TDP-43 and FUS have identified the phospholipase D (Pld) pathway as a key regulator of ALS-related phenotypes in the fruit fly Drosophila melanogaster [M. W. Kankel et al., Genetics 215, 747-766 (2020)]. Here, we report the results of our search for downstream targets of the enzymatic product of Pld, phosphatidic acid. We identify two conserved negative regulators of the cAMP/PKA signaling pathway, the phosphodiesterase dunce and the inhibitory subunit PKA-R2, as modifiers of pathogenic phenotypes resulting from overexpression of the Drosophila TDP-43 ortholog TBPH. We show that knockdown of either of these genes results in a mitigation of both TBPH aggregation and mislocalization in larval motor neuron cell bodies, as well as an amelioration of adult-onset motor defects and shortened lifespan induced by TBPH. We determine that PKA kinase activity is downstream of both TBPH and Pld and that overexpression of the PKA target CrebA can rescue TBPH mislocalization. These findings suggest a model whereby increasing cAMP/PKA signaling can ameliorate the molecular and functional effects of pathological TDP-43.
    Keywords:  ALS; TDP-43; cAMP/PKA signaling; neurodegeneration; proteinopathy
    DOI:  https://doi.org/10.1073/pnas.2400732121
  3. Mol Brain. 2024 Jun 05. 17(1): 32
    TDP43 interacts with MLH1 and MSH6 proteins in a DNA damage-inducible manner.
    Vincent E Provasek, Manohar Kodavati, Brandon Kim, Joy Mitra, Muralidhar L Hegde.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double-strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that the TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complementary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 h treatment of 10 μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS-affected neurons.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Co-immunoprecipitation (CoIP); DNA double-strand breaks (DSBs); DNA mismatch repair (MMR); Neurodegeneration; Proximity ligation assay (PLA); TDP-43
    DOI:  https://doi.org/10.1186/s13041-024-01108-3
  4. Sci Transl Med. 2024 Jun 05. 16(750): eadj7308
    Peripheral expression of brain-penetrant progranulin rescues pathologies in mouse models of frontotemporal lobar degeneration.
    Marvin Reich, Matthew J Simon, Beate Polke, Iñaki Paris, Georg Werner, Christian Schrader, Lena Spieth, Sonnet S Davis, Sophie Robinson, Gabrielly Lunkes de Melo, Lennart Schlaphoff, Katrin Buschmann, Stefan Berghoff, Todd Logan, Brigitte Nuscher, Lis de Weerd, Dieter Edbauer, Mikael Simons, Jung H Suh, Thomas Sandmann, Mihalis S Kariolis, Sarah L DeVos, Joseph W Lewcock, Dominik Paquet, Anja Capell, Gilbert Di Paolo, Christian Haass.
      Progranulin (PGRN) haploinsufficiency is a major risk factor for frontotemporal lobar degeneration with TAR DNA-binding protein 43 (TDP-43) pathology (FTLD-GRN). Multiple therapeutic strategies are in clinical development to restore PGRN in the CNS, including gene therapy. However, a limitation of current gene therapy approaches aimed to alleviate FTLD-associated pathologies may be their inefficient brain exposure and biodistribution. We therefore developed an adeno-associated virus (AAV) targeting the liver (L) to achieve sustained peripheral expression of a transferrin receptor (TfR) binding, brain-penetrant (b) PGRN variant [AAV(L):bPGRN] in two mouse models of FTLD-GRN, namely, Grn knockout and GrnxTmem106b double knockout mice. This therapeutic strategy avoids potential safety and biodistribution issues of CNS-administered AAVs and maintains sustained concentrations of PGRN in the brain after a single dose. AAV(L):bPGRN treatment reduced several FTLD-GRN-associated pathologies including severe motor function deficits, aberrant TDP-43 phosphorylation, dysfunctional protein degradation, lipid metabolism, gliosis, and neurodegeneration in the brain. The potential translatability of our findings was tested in an in vitro model using cocultured human induced pluripotent stem cell (hiPSC)-derived microglia lacking PGRN and TMEM106B and wild-type hiPSC-derived neurons. As in mice, aberrant TDP-43, lysosomal dysfunction, and neuronal loss were ameliorated after treatment with exogenous TfR-binding protein transport vehicle fused to PGRN (PTV:PGRN). Together, our studies suggest that peripherally administered brain-penetrant PGRN replacement strategies ameliorate FTLD-GRN relevant phenotypes including TDP-43 pathology, neurodegeneration, and behavioral deficits. Our data provide preclinical proof of concept for the use of this AAV platform for treatment of FTLD-GRN and potentially other CNS disorders.
    DOI:  https://doi.org/10.1126/scitranslmed.adj7308
  5. Dis Model Mech. 2024 Jun 03. pii: dmm.050570. [Epub ahead of print]
    Hyperactivation of MEK1 in cortical glutamatergic neurons results in projection axon deficits and aberrant motor learning.
    George R Bjorklund, Katherina P Rees, Kavya Balasubramanian, Lauren T Hewitt, Kenji Nishimura, Jason M Newbern.
      Abnormal Extracellular Regulated Kinase 1/2 (ERK1/2) signaling is linked to multiple neurodevelopmental diseases, especially the RASopathies, which typically exhibit ERK1/2 hyperactivation in neurons and non-neuronal cells. To better understand how excitatory neuron-autonomous ERK1/2 activity regulates forebrain development, we conditionally expressed hyperactive MEK1S217/221E in cortical excitatory neurons. MEK1S217/221E expression led to persistent hyperactivation of ERK1/2 in cortical axons, but not in soma/nuclei. We noted reduced axonal arborization in multiple target domains in mutants and reduced expression of the activity dependent gene, ARC. These changes did not lead to deficits in voluntary locomotion or accelerating rotarod performance. However, skilled motor learning in a single-pellet retrieval task was significantly diminished in these MEK1S217/221E mutants. Restriction of MEK1S217/221E expression to layer V cortical neurons recapitulated axonal outgrowth deficits, but did not effect motor learning. These results suggest that cortical excitatory neuron-autonomous hyperactivation of MEK1 is sufficient to drive deficits in axon outgrowth, which coincide with reduced ARC expression, and deficits in skilled motor learning. Our data indicate that neuron-autonomous decreases in long-range axonal outgrowth may be a key aspect of neuropathogenesis in RASopathies.
    Keywords:  Axon; Connectivity; Cortex; Development; Kinase; RASopathy
    DOI:  https://doi.org/10.1242/dmm.050570
  6. Exp Mol Med. 2024 Jun 03.
    Advances and challenges in modeling inherited peripheral neuropathies using iPSCs.
    Jonas Van Lent, Robert Prior, Gonzalo Pérez Siles, Anthony N Cutrupi, Marina L Kennerson, Tim Vangansewinkel, Esther Wolfs, Bipasha Mukherjee-Clavin, Zachary Nevin, Luke Judge, Bruce Conklin, Henna Tyynismaa, Alex J Clark, David L Bennett, Ludo Van Den Bosch, Mario Saporta, Vincent Timmerman.
      Inherited peripheral neuropathies (IPNs) are a group of diseases associated with mutations in various genes with fundamental roles in the development and function of peripheral nerves. Over the past 10 years, significant advances in identifying molecular disease mechanisms underlying axonal and myelin degeneration, acquired from cellular biology studies and transgenic fly and rodent models, have facilitated the development of promising treatment strategies. However, no clinical treatment has emerged to date. This lack of treatment highlights the urgent need for more biologically and clinically relevant models recapitulating IPNs. For both neurodevelopmental and neurodegenerative diseases, patient-specific induced pluripotent stem cells (iPSCs) are a particularly powerful platform for disease modeling and preclinical studies. In this review, we provide an update on different in vitro human cellular IPN models, including traditional two-dimensional monoculture iPSC derivatives, and recent advances in more complex human iPSC-based systems using microfluidic chips, organoids, and assembloids.
    DOI:  https://doi.org/10.1038/s12276-024-01250-x
  7. Alzheimers Dement. 2024 Jun 02.
    The presenilin 1 mutation P436S causes familial Alzheimer's disease with elevated Aβ43 and atypical clinical manifestations.
    Charles Arber, Christopher R S Belder, Filip Tomczuk, Rebecca Gabriele, Yazead Buhidma, Clíona Farrell, Antoinette O'Connor, Helen Rice, Tammaryn Lashley, Nick C Fox, Natalie S Ryan, Selina Wray.
       INTRODUCTION: Familial Alzheimer's disease (fAD) is heterogeneous in terms of age at onset and clinical presentation. A greater understanding of the pathogenicity of fAD variants and how these contribute to heterogeneity will enhance our understanding of the mechanisms of AD more widely.
    METHODS: To determine the pathogenicity of the unclassified PSEN1 P436S mutation, we studied an expanded kindred of eight affected individuals, with magnetic resonance imaging (MRI) (two individuals), patient-derived induced pluripotent stem cell (iPSC) models (two donors), and post-mortem histology (one donor).
    RESULTS: An autosomal dominant pattern of inheritance of fAD was seen, with an average age at symptom onset of 46 years and atypical features. iPSC models and post-mortem tissue supported high production of amyloid beta 43 (Aβ43). PSEN1 peptide maturation was unimpaired.
    DISCUSSION: We confirm that the P436S mutation in PSEN1 causes atypical fAD. The location of the mutation in the critical PSEN1 proline-alanine-leucine-proline (PALP) motif may explain the early age at onset despite appropriate protein maturation.
    HIGHLIGHTS: PSEN1 P436S mutations cause familial Alzheimer's disease. This mutation is associated with atypical clinical presentation. Induced pluripotent stem cells (iPSCs) and post-mortem studies support increased amyloid beta (Aβ43) production. Early age at onset highlights the importance of the PALP motif in PSEN1 function.
    Keywords:  AD; Aβ; PALP; PSEN1; familial Alzheimer's disease; iPSC
    DOI:  https://doi.org/10.1002/alz.13904
  8. Cell Death Dis. 2024 Jun 07. 15(6): 399
    DDAH-1 maintains endoplasmic reticulum-mitochondria contacts and protects dopaminergic neurons in Parkinson's disease.
    Yichen Zhao, Weiwei Shen, Minjie Zhang, Min Guo, Yunxiao Dou, Sida Han, Jintai Yu, Mei Cui, Yanxin Zhao.
      The loss of dopaminergic neurons in the substantia nigra is a hallmark of pathology in Parkinson's disease (PD). Dimethylarginine dimethylaminohydrolase-1 (DDAH-1) is the critical enzyme responsible for the degradation of asymmetric dimethylarginine (ADMA) which inhibits nitric oxide (NO) synthase and has been implicated in neurodegeneration. Mitochondrial dysfunction, particularly in the mitochondria-associated endoplasmic reticulum membrane (MAM), plays a critical role in this process, although the specific molecular target has not yet been determined. This study aims to examine the involvement of DDAH-1 in the nigrostriatal dopaminergic pathway and PD pathogenesis. The distribution of DDAH-1 in the brain and its colocalization with dopaminergic neurons were observed. The loss of dopaminergic neurons and aggravated locomotor disability after rotenone (ROT) injection were showed in the DDAH-1 knockout rat. L-arginine (ARG) and NO donors were employed to elucidate the role of NO respectively. In vitro, we investigated the effects of DDAH-1 knockdown or overexpression on cell viability and mitochondrial functions, as well as modulation of ADMA/NO levels using ADMA or ARG. MAM formation was assessed by the Mitofusin2 oligomerization and the mitochondrial ubiquitin ligase (MITOL) phosphorylation. We found that DDAH-1 downregulation resulted in enhanced cell death and mitochondrial dysfunctions, accompanied by elevated ADMA and reduced NO levels. However, the recovered NO level after the ARG supplement failed to exhibit a protective effect on mitochondrial functions and partially restored cell viability. DDAH-1 overexpression prevented ROT toxicity, while ADMA treatment attenuated these protective effects. The declines of MAM formation in ROT-treated cells were exacerbated by DDAH-1 downregulation via reduced MITOL phosphorylation, which was reversed by DDAH-1 overexpression. Together, the abundant expression of DDAH-1 in nigral dopaminergic neurons may exert neuroprotective effects by maintaining MAM formation and mitochondrial function probably via ADMA, indicating the therapeutic potential of targeting DDAH-1 for PD.
    DOI:  https://doi.org/10.1038/s41419-024-06772-w
  9. Nat Commun. 2024 Jun 07. 15(1): 4867
    Stabilization of V1 interneuron-motor neuron connectivity ameliorates motor phenotype in a mouse model of ALS.
    Santiago Mora, Anna Stuckert, Rasmus von Huth Friis, Kimberly Pietersz, Gith Noes-Holt, Roser Montañana-Rosell, Haoyu Wang, Andreas Toft Sørensen, Raghavendra Selvan, Joost Verhaagen, Ilary Allodi.
      Loss of connectivity between spinal V1 inhibitory interneurons and motor neurons is found early in disease in the SOD1G93A mice. Such changes in premotor inputs can contribute to homeostatic imbalance of motor neurons. Here, we show that the Extended Synaptotagmin 1 (Esyt1) presynaptic organizer is downregulated in V1 interneurons. V1 restricted overexpression of Esyt1 rescues inhibitory synapses, increases motor neuron survival, and ameliorates motor phenotypes. Two gene therapy approaches overexpressing ESYT1 were investigated; one for local intraspinal delivery, and the other for systemic administration using an AAV-PHP.eB vector delivered intravenously. Improvement of motor functions is observed in both approaches, however systemic administration appears to significantly reduce onset of motor impairment in the SOD1G93A mice in absence of side effects. Altogether, we show that stabilization of V1 synapses by ESYT1 overexpression has the potential to improve motor functions in ALS, demonstrating that interneurons can be a target to attenuate ALS symptoms.
    DOI:  https://doi.org/10.1038/s41467-024-48925-7
  10. Amyotroph Lateral Scler Frontotemporal Degener. 2024 Jun 03. 1-2
    International network for ALS research and care (INARC).
    Juliette Foucher, Tommy M Bunte, Vanessa Bertone, Romy L Verschoor, Mathias Couillard, Corey Straub, Angela Genge, Caroline Ingre, Leonard H van den Berg.
      The International Network for Amyotrophic Lateral Sclerosis (ALS) Research and Care (INARC) was founded in 2022. INARC's main goals are to offer a platform dedicated to staff members for ALS clinics and research teams who are not physicians. By nurturing experience and expertise exchanges to improve problem solving skills, the ultimate goal is to increase the standard ALS care and research. This brief report aims to describe the formation of INARC, the 2023 INARC meeting, as well as to report topics discussed, lessons learned and challenges raised by INARC members.
    Keywords:  Amyotrophic lateral sclerosis; cooperation; international; network; report
    DOI:  https://doi.org/10.1080/21678421.2024.2362850
  11. J Neurosci. 2024 Jun 03. pii: e2334232024. [Epub ahead of print]
    Rab6-mediated polarized transport of synaptic vesicle precursors is essential for the establishment of neuronal polarity and brain formation.
    Yu Zhang, Masataka Kunii, Manabu Taniguchi, Shin-Ichiro Yoshimura, Akihiro Harada.
      Neurons are highly polarized cells that are composed of a single axon and multiple dendrites. Axon-dendrite polarity is essential for proper tissue formation and brain functions. Intracellular protein transport plays an important role in the establishment of neuronal polarity. However, the regulatory mechanism of polarized transport remains unclear. Here, we show that Rab6, a small GTPase that acts on the regulation of intracellular vesicular trafficking, plays key roles in neuronal polarization and brain development. Central nervous system-specific Rab6a/b double knockout (Rab6 DKO) mice of both sexes exhibit severe dysplasia of the neocortex and the cerebellum. In the Rab6 DKO neocortex, impaired axonal extension of neurons results in hypoplasia of the intermediate zone. In vitro, deletion of Rab6a and Rab6b in cultured neurons from both sexes causes the abnormal accumulation of synaptic vesicle precursors (SVPs) adjacent to the Golgi apparatus, which leads to defects in axonal extension and the loss of axon-dendrite polarity. Moreover, Rab6 DKO causes significant expansion of lysosomes in the soma in neurons. Overall, our results reveal that Rab6-mediated polarized transport of SVPs is crucial for neuronal polarization and subsequent brain formation.Significance Statement Elucidation of the regulatory mechanism underlying neuronal polarization is crucial to understanding neuron development and brain formation. Intracellular polarized transport plays an essential role in the establishment of axon-dendrite polarity. In this study, by using central nervous system-specific Rab6a/b double knockout mice and primary cultured neurons, we showed the physiological role of Rab6 in neuronal polarization and subsequent neocortical IZ formation in vivo. Mechanistically, we revealed that Rab6 regulates the post-Golgi anterograde transport of synaptic vesicle precursors, which contributes to axonal extension in developing neurons.
    DOI:  https://doi.org/10.1523/JNEUROSCI.2334-23.2024
  12. Res Sq. 2024 May 21. pii: rs.3.rs-4439430. [Epub ahead of print]
    TDP43 Interacts with MLH1 and MSH6 Proteins in A DNA Damage-Inducible Manner.
    Vincent E Provasek, Manohar Kodavati, Brandon Kim, Joy Mitra, Muralidhar L Hegde.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects the motor neuron. One aspect of the neuropathology involved in ALS includes increased genomic damage and impaired DNA repair capability. The TAR-DNA binding protein 43 (TDP43) has been associated with both sporadic and familial forms of ALS, and is typically observed as cytosolic mislocalization of protein aggregates, termed TDP43 proteinopathy. TDP43 is a ubiquitous RNA/DNA binding protein with functional implications in a wide range of disease processes, including the repair of DNA double strand breaks (DSBs). While TDP43 is widely known to regulate RNA metabolism, our lab has reported it also functions directly at the protein level to facilitate DNA repair. Here, we show that TDP43 protein interacts with DNA mismatch repair (MMR) proteins MLH1 and MSH6 in a DNA damage-inducible manner. We utilized differentiated SH-SY5Y neuronal cultures to identify this inducible relationship using complimentary approaches of proximity ligation assay (PLA) and co-immunoprecipitation (CoIP) assay. We observed that signals of TDP43 interaction with MLH1 and MSH6 increased significantly following a 2 hr treatment of 10μM methylmethanesulfonate (MMS), a DNA alkylating agent used to induce MMR repair. Likewise, we observed this effect was abolished in cell lines treated with siRNA directed against TDP43. Finally, we demonstrated these protein interactions were significantly increased in lumbar spinal cord samples of ALS-affected patients compared to age-matched controls. These results will inform our future studies to understand the mechanisms and consequences of this TDP43-MMR interaction in the context of ALS affected neurons.
    DOI:  https://doi.org/10.21203/rs.3.rs-4439430/v1
  13. Mol Neurobiol. 2024 Jun 03.
    The Current Potential Pathogenesis of Amyotrophic Lateral Sclerosis.
    Shishi Jiang, Renshi Xu.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease mainly characterized by the accumulation of ubiquitinated proteins in the affected motor neurons. At present, the accurate pathogenesis of ALS remains unclear and there are still no effective treatment measures for ALS. The potential pathogenesis of ALS mainly includes the misfolding of some pathogenic proteins, the genetic variation, mitochondrial dysfunction, autophagy disorders, neuroinflammation, the misregulation of RNA, the altered axonal transport, and gut microbial dysbiosis. Exploring the pathogenesis of ALS is a critical step in searching for the effective therapeutic approaches. The current studies suggested that the genetic variation, gut microbial dysbiosis, the activation of glial cells, and the transportation disorder of extracellular vesicles may play some important roles in the pathogenesis of ALS. This review conducts a systematic review of these current potential promising topics closely related to the pathogenesis of ALS; it aims to provide some new evidences and clues for searching the novel treatment measures of ALS.
    Keywords:  Amyotrophic lateral sclerosis; Extracellular vesicles; Gastrointestinal microbiome; Genetic mutations; Neuroglia
    DOI:  https://doi.org/10.1007/s12035-024-04269-3
  14. Nat Nanotechnol. 2024 Jun 07.
    Polystyrene nanoparticles trigger aberrant condensation of TDP-43 and amyotrophic lateral sclerosis-like symptoms.
    Hang Sun, Bingwei Yang, Qiong Li, Xiaokang Zhu, Erqun Song, Cong Liu, Yang Song, Guibin Jiang.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the dysfunction and progressive death of cerebral and spinal motor neurons. Preliminary epidemiological research has hinted at a relationship between environmental risks and the escalation of ALS, but the underlying reasons remain mostly mysterious. Here we show that nanosize polystyrene plastics (PS) induce ALS-like symptoms and illustrate the related molecular mechanism. When exposed to PS, cells endure internal oxidative stress, which leads to the aggregation of TAR DNA-binding protein 43 kDa (TDP-43), triggering ALS-like characteristics. In addition, the oxidized heat shock protein 70 fails to escort TDP-43 back to the nucleus. The cytoplasmic accumulation of TDP-43 facilitates the formation of a complex between PS and TDP-43, enhancing the condensation and solidification of TDP-43. These findings are corroborated through in silico and in vivo assays. Altogether, our work illustrates a unique toxicological mechanism induced by nanoparticles and provides insights into the connection between environmental pollution and neurodegenerative disorders.
    DOI:  https://doi.org/10.1038/s41565-024-01683-5
  15. Med Genet. 2022 Jun;34(2): 103-116
    Molecular mechanisms defining penetrance of LRRK2-associated Parkinson's disease.
    Joanne Trinh, Emma L Schymanski, Semra Smajic, Meike Kasten, Esther Sammler, Anne Grünewald.
      Mutations in Leucine-rich repeat kinase 2 (LRRK2) are the most frequent cause of dominantly inherited Parkinson's disease (PD). LRRK2 mutations, among which p.G2019S is the most frequent, are inherited with reduced penetrance. Interestingly, the disease risk associated with LRRK2 G2019S can vary dramatically depending on the ethnic background of the carrier. While this would suggest a genetic component in the definition of LRRK2-PD penetrance, only few variants have been shown to modify the age at onset of patients harbouring LRRK2 mutations, and the exact cellular pathways controlling the transition from a healthy to a diseased state currently remain elusive. In light of this knowledge gap, recent studies also explored environmental and lifestyle factors as potential modifiers of LRRK2-PD. In this article, we (i) describe the clinical characteristics of LRRK2 mutation carriers, (ii) review known genes linked to LRRK2-PD onset and (iii) summarize the cellular functions of LRRK2 with particular emphasis on potential penetrance-related molecular mechanisms. This section covers LRRK2's involvement in Rab GTPase and immune signalling as well as in the regulation of mitochondrial homeostasis and dynamics. Additionally, we explored the literature with regard to (iv) lifestyle and (v) environmental factors that may influence the penetrance of LRRK2 mutations, with a view towards further exposomics studies. Finally, based on this comprehensive overview, we propose potential future in vivo, in vitro and in silico studies that could provide a better understanding of the processes triggering PD in individuals with LRRK2 mutations.
    Keywords:  LRRK2; Parkinson’s disease; Rab signalling; environment; genetic modifiers; mitochondria; penetrance; toxin exposure
    DOI:  https://doi.org/10.1515/medgen-2022-2127
  16. Sci Adv. 2024 Jun 07. 10(23): eadn7191
    Mechanism of human PINK1 activation at the TOM complex in a reconstituted system.
    Olawale G Raimi, Hina Ojha, Kenneth Ehses, Verena Dederer, Sven M Lange, Cristian Polo Rivera, Tom D Deegan, Yinchen Chen, Melanie Wightman, Rachel Toth, Karim P M Labib, Sebastian Mathea, Neil Ranson, Rubén Fernández-Busnadiego, Miratul M K Muqit.
      Loss-of-function mutations in PTEN-induced kinase 1 (PINK1) are a frequent cause of early-onset Parkinson's disease (PD). Stabilization of PINK1 at the translocase of outer membrane (TOM) complex of damaged mitochondria is critical for its activation. The mechanism of how PINK1 is activated in the TOM complex is unclear. Here, we report that co-expression of human PINK1 and all seven TOM subunits in Saccharomyces cerevisiae is sufficient for PINK1 activation. We use this reconstitution system to systematically assess the role of each TOM subunit toward PINK1 activation. We unambiguously demonstrate that the TOM20 and TOM70 receptor subunits are required for optimal PINK1 activation and map their sites of interaction with PINK1 using AlphaFold structural modeling and mutagenesis. We also demonstrate an essential role of the pore-containing subunit TOM40 and its structurally associated subunits TOM7 and TOM22 for PINK1 activation. These findings will aid in the development of small-molecule activators of PINK1 as a therapeutic strategy for PD.
    DOI:  https://doi.org/10.1126/sciadv.adn7191
  17. Sci Adv. 2024 Jun 07. 10(23): eadj0385
    A dynamic in vitro model of Down syndrome neurogenesis with trisomy 21 gene dosage correction.
    Prakhar Bansal, Erin C Banda, Heather R Glatt-Deeley, Christopher E Stoddard, Jeremy W Linsley, Neha Arora, Cécile Deleschaux, Darcy T Ahern, Yuvabharath Kondaveeti, Rachael E Massey, Michael Nicouleau, Shijie Wang, Miguel Sabariego-Navarro, Mara Dierssen, Steven Finkbeiner, Stefan F Pinter.
      Excess gene dosage from chromosome 21 (chr21) causes Down syndrome (DS), spanning developmental and acute phenotypes in terminal cell types. Which phenotypes remain amenable to intervention after development is unknown. To address this question in a model of DS neurogenesis, we derived trisomy 21 (T21) human induced pluripotent stem cells (iPSCs) alongside, otherwise, isogenic euploid controls from mosaic DS fibroblasts and equipped one chr21 copy with an inducible XIST transgene. Monoallelic chr21 silencing by XIST is near-complete and irreversible in iPSCs. Differential expression reveals that T21 neural lineages and iPSCs share suppressed translation and mitochondrial pathways and activate cellular stress responses. When XIST is induced before the neural progenitor stage, T21 dosage correction suppresses a pronounced skew toward astrogenesis in neural differentiation. Because our transgene remains inducible in postmitotic T21 neurons and astrocytes, we demonstrate that XIST efficiently represses genes even after terminal differentiation, which will empower exploration of cell type-specific T21 phenotypes that remain responsive to chr21 dosage.
    DOI:  https://doi.org/10.1126/sciadv.adj0385
  18. Cell. 2024 Jun 03. pii: S0092-8674(24)00519-1. [Epub ahead of print]
    Capturing totipotency in human cells through spliceosomal repression.
    Shiyu Li, Min Yang, Hui Shen, Li Ding, Xuehui Lyu, Kexin Lin, Jennie Ong, Peng Du.
      The cleavage of zygotes generates totipotent blastomeres. In human 8-cell blastomeres, zygotic genome activation (ZGA) occurs to initiate the ontogenesis program. However, capturing and maintaining totipotency in human cells pose significant challenges. Here, we realize culturing human totipotent blastomere-like cells (hTBLCs). We find that splicing inhibition can transiently reprogram human pluripotent stem cells into ZGA-like cells (ZLCs), which subsequently transition into stable hTBLCs after long-term passaging. Distinct from reported 8-cell-like cells (8CLCs), both ZLCs and hTBLCs widely silence pluripotent genes. Interestingly, ZLCs activate a particular group of ZGA-specific genes, and hTBLCs are enriched with pre-ZGA-specific genes. During spontaneous differentiation, hTBLCs re-enter the intermediate ZLC stage and further generate epiblast (EPI)-, primitive endoderm (PrE)-, and trophectoderm (TE)-like lineages, effectively recapitulating human pre-implantation development. Possessing both embryonic and extraembryonic developmental potency, hTBLCs can autonomously generate blastocyst-like structures in vitro without external cell signaling. In summary, our study provides key criteria and insights into human cell totipotency.
    Keywords:  ZGA-like cells; blastocyst-like structure; blastomere; pluripotent; splicing inhibition; stem cell culture; totipotency; totipotent blastomere-like cells; zygotic genomic activation
    DOI:  https://doi.org/10.1016/j.cell.2024.05.010
  19. Brain Commun. 2024 ;6(3): fcae184
    Spinal cord neurone loss and foot placement changes in a rat knock-in model of amyotrophic lateral sclerosis Type 8.
    Brenda Murage, Han Tan, Tomoji Mashimo, Mandy Jackson, Paul A Skehel.
      Amyotrophic lateral sclerosis is an age-dependent cell type-selective degenerative disease. Genetic studies indicate that amyotrophic lateral sclerosis is part of a spectrum of disorders, ranging from spinal muscular atrophy to frontotemporal dementia that share common pathological mechanisms. Amyotrophic lateral sclerosis Type 8 is a familial disease caused by mis-sense mutations in VAPB. VAPB is localized to the cytoplasmic surface of the endoplasmic reticulum, where it serves as a docking point for cytoplasmic proteins and mediates inter-organelle interactions with the endoplasmic reticulum membrane. A gene knock-in model of amyotrophic lateral sclerosis Type 8 based on the VapBP56S mutation and VapB gene deletion has been generated in rats. These animals display a range of age-dependent phenotypes distinct from those previously reported in mouse models of amyotrophic lateral sclerosis Type 8. A loss of motor neurones in VapBP56S/+ and VapBP56S/P56S animals is indicated by a reduction in the number of large choline acetyl transferase-staining cells in the spinal cord. VapB-/- animals exhibit a relative increase in cytoplasmic TDP-43 levels compared with the nucleus, but no large protein aggregates. Concomitant with these spinal cord pathologies VapBP56S/+ , VapBP56S/P56S and VapB-/- animals exhibit age-dependent changes in paw placement and exerted pressures when traversing a CatWalk apparatus, consistent with a somatosensory dysfunction. Extramotor dysfunction is reported in half the cases of motor neurone disease, and this is the first indication of an associated sensory dysfunction in a rodent model of amyotrophic lateral sclerosis. Different rodent models may offer complementary experimental platforms with which to understand the human disease.
    Keywords:  ALS8; VAPB; motor neurone disease
    DOI:  https://doi.org/10.1093/braincomms/fcae184
  20. Dig Dis Sci. 2024 Jun 07.
    Biphenotypic Cells and α-Synuclein Accumulation in Enteric Neurons of Leucine-Rich Repeat Kinase 2 Knockout Mice.
    Tatsunori Maekawa, Ryuichi Motokawa, Rei Kawashima, Shun Tamaki, Yusuke Hara, Fumitaka Kawakami, Takafumi Ichikawa.
       BACKGROUND: Leucine-rich repeat kinase 2 is a molecule that is responsible for familial Parkinson's disease. Our previous findings revealed that leucine-rich repeat kinase 2 is expressed in the enteric nervous system. However, which cells in the enteric nervous system express leucine-rich repeat kinase 2 and whether leucine-rich repeat kinase 2 is associated with the structure of the enteric nervous system remain unclear. The enteric nervous system is remarkable because some patients with Parkinson's disease experience gastrointestinal symptoms before developing motor symptoms.
    AIMS: We established a leucine-rich repeat kinase 2 reporter mouse model and performed immunostaining in leucine-rich repeat kinase 2 knockout mice.
    METHODS: Longitudinal muscle containing the myenteric plexus prepared from leucine-rich repeat kinase 2 reporter mice was analyzed by immunostaining using anti-green fluorescent protein (GFP) antibody. Immunostaining using several combinations of antibodies characterizing enteric neurons and glial cells was performed on intestinal preparations from leucine-rich repeat kinase 2 knockout mice.
    RESULTS: GFP expression in the reporter mice was predominantly in enteric glial cells rather than in enteric neurons. Immunostaining revealed that differences in the structure and proportion of major immunophenotypic cells were not apparent in the knockout mice. Interestingly, the number of biphenotypic cells expressing the neuronal and glial cell markers increased in the leucine-rich repeat kinase 2 knockout mice. Moreover, there was accumulation of α-synuclein in the knockout mice.
    CONCLUSIONS: Our present findings suggest that leucine-rich repeat kinase 2 is a newly recognized molecule that potentially regulates the integrity of enteric nervous system and enteric α-synuclein accumulation.
    Keywords:   Lrrk2 ; Enteric nervous system; Parkinson’s disease; α-Synuclein
    DOI:  https://doi.org/10.1007/s10620-024-08494-7
  21. FASEB J. 2024 Jun 15. 38(11): e23720
    Impaired cathepsin D in retinal pigment epithelium cells mediates Stargardt disease pathogenesis.
    Eunice Sze Yin Ng, Jane Hu, Zhichun Jiang, Roxana A Radu.
      Recessive Stargardt disease (STGD1) is an inherited juvenile maculopathy caused by mutations in the ABCA4 gene, for which there is no suitable treatment. Loss of functional ABCA4 in the retinal pigment epithelium (RPE) alone, without contribution from photoreceptor cells, was shown to induce STGD1 pathology. Here, we identified cathepsin D (CatD), the primary RPE lysosomal protease, as a key molecular player contributing to endo-lysosomal dysfunction in STGD1 using a newly developed "disease-in-a-dish" RPE model from confirmed STGD1 patients. Induced pluripotent stem cell (iPSC)-derived RPE originating from three STGD1 patients exhibited elevated lysosomal pH, as previously reported in Abca4-/- mice. CatD protein maturation and activity were impaired in RPE from STGD1 patients and Abca4-/- mice. Consequently, STGD1 RPE cells have reduced photoreceptor outer segment degradation and abnormal accumulation of α-synuclein, the natural substrate of CatD. Furthermore, dysfunctional ABCA4 in STGD1 RPE cells results in intracellular accumulation of autofluorescent material and phosphatidylethanolamine (PE). The altered distribution of PE associated with the internal membranes of STGD1 RPE cells presumably compromises LC3-associated phagocytosis, contributing to delayed endo-lysosomal degradation activity. Drug-mediated re-acidification of lysosomes in the RPE of STGD1 restores CatD functional activity and reduces the accumulation of immature CatD protein loads. This preclinical study validates the contribution of CatD deficiencies to STGD1 pathology and provides evidence for an efficacious therapeutic approach targeting RPE cells. Our findings support a cell-autonomous RPE-driven pathology, informing future research aimed at targeting RPE cells to treat ABCA4-mediated retinopathies.
    Keywords:  cathepsin D; endo‐lysosome; phagocytosis; phosphatidylethanolamine; recessive Stargardt disease; retinal pigment epithelium
    DOI:  https://doi.org/10.1096/fj.202400210RR
  22. Neurol Genet. 2024 Jun;10(3): e200160
    TARDBP Mutations in Facial-Onset Sensory and Motor Neuronopathy.
    Vincent Picher-Martel, Suma Babu, Anthony A Amato.
       Objectives: Facial-onset sensory and motor neuronopathy (FOSMN) is a rare neuromuscular disorder characterized by progressive facial sensory impairment followed by motor dysfunction in a rostro-caudal distribution. FOSMN is clinically and pathologically associated with amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). In contrast to ALS/FTD, the genetic profile of patients with FOSMN and the role of genetic testing are poorly defined.
    Methods: A 66-year-old woman was evaluated in our neuromuscular clinic for progressive facial pain, dysphagia, and dysarthria. Her diagnostic evaluation included brain and cervical MRI, nerve conduction studies and EMG, and an ALS/FTD next-generation sequencing panel.
    Results: The patient was diagnosed with FOSMN, and we identified a N390D variant in transactive response DNA-binding protein (TDP-43/TARDBP). This variant has never been reported in FOSMN but was previously reported in 2 cases of ALS, and a N390S variant was also previously reported in FOSMN. A review of the literature revealed that TARDBP mutations are overrepresented in patients with FOSMN compared with patients with ALS/FTD. By contrast, other common familial forms of ALS, including C9ORF72 or SOD1, are respectively absent or rare in FOSMN.
    Discussion: FOSMN is pathologically and genetically associated with TDP-43. Therefore, ALS genetic testing that includes specifically TARDBP should be considered in patients with FOSMN.
    DOI:  https://doi.org/10.1212/NXG.0000000000200160
  23. J Exp Med. 2024 Aug 05. pii: e20231512. [Epub ahead of print]221(8):
    Coxsackievirus A10 impairs nail regeneration and induces onychomadesis by mimicking DKK1 to attenuate Wnt signaling.
    Yingzi Cui, Qiaoni Shi, Pu Song, Jianyu Tong, Zhimin Cheng, Hangchuan Zhang, Xiaodan Wang, Yuxuan Zheng, Yao Wu, Meng Wan, Shihua Li, Xin Zhao, Zhou Tong, Zhengquan Yu, Shan Gao, Ye-Guang Chen, George Fu Gao.
      Coxsackievirus A10 (CV-A10) infection, a prominent cause of childhood hand-foot-and-mouth disease (HFMD), frequently manifests with the intriguing phenomenon of onychomadesis, characterized by nail shedding. However, the underlying mechanism is elusive. Here, we found that CV-A10 infection in mice could suppress Wnt/β-catenin signaling by restraining LDL receptor-related protein 6 (LRP6) phosphorylation and β-catenin accumulation and lead to onychomadesis. Mechanistically, CV-A10 mimics Dickkopf-related protein 1 (DKK1) to interact with Kringle-containing transmembrane protein 1 (KRM1), the CV-A10 cellular receptor. We further found that Wnt agonist (GSK3β inhibitor) CHIR99021 can restore nail stem cell differentiation and protect against nail shedding. These findings provide novel insights into the pathogenesis of CV-A10 and related viruses in onychomadesis and guide prognosis assessment and clinical treatment of the disease.
    DOI:  https://doi.org/10.1084/jem.20231512
  24. J Vis Exp. 2024 May 17.
    Differentiation of Enteric Nervous System Lineages from Human Pluripotent Stem Cells.
    Homa Majd, Mikayla N Richter, Ryan M Samuel, Ali Kalantari, Jonathan T Ramirez, Faranak Fattahi.
      The human enteric nervous system, ENS, is a large network of glial and neuronal cell types with remarkable neurotransmitter diversity. The ENS controls bowel motility, enzyme secretion, and nutrient absorption and interacts with the immune system and the gut microbiome. Consequently, developmental and acquired defects of the ENS are responsible for many human diseases and may contribute to symptoms of Parkinson's disease. Limitations in animal model systems and access to primary tissue pose significant experimental challenges in studies of the human ENS. Here, a detailed protocol is presented for effective in vitro derivation of the ENS lineages from human pluripotent stem cells, hPSC, using defined culture conditions. Our protocol begins with directed differentiation of hPSCs to enteric neural crest cells within 15 days and yields diverse subtypes of functional enteric neurons within 30 days. This platform provides a scalable resource for developmental studies, disease modeling, drug discovery, and regenerative applications.
    DOI:  https://doi.org/10.3791/66133
  25. Lab Chip. 2024 Jun 06.
    A fluid-walled microfluidic platform for human neuron microcircuits and directed axotomy.
    Federico Nebuloni, Quyen B Do, Peter R Cook, Edmond J Walsh, Richard Wade-Martins.
      In our brains, different neurons make appropriate connections; however, there remain few in vitro models of such circuits. We use an open microfluidic approach to build and study neuronal circuits in vitro in ways that fit easily into existing bio-medical workflows. Dumbbell-shaped circuits are built in minutes in standard Petri dishes; the aqueous phase is confined by fluid walls - interfaces between cell-growth medium and an immiscible fluorocarbon, FC40. Conditions are established that ensure post-mitotic neurons derived from human induced pluripotent stem cells (iPSCs) plated in one chamber of a dumbbell remain where deposited. After seeding cortical neurons on one side, axons grow through the connecting conduit to ramify amongst striatal neurons on the other - an arrangement mimicking unidirectional cortico-striatal connectivity. We also develop a moderate-throughput non-contact axotomy assay. Cortical axons in conduits are severed by a media jet; then, brain-derived neurotrophic factor and striatal neurons in distal chambers promote axon regeneration. As additional conduits and chambers are easily added, this opens up the possibility of mimicking complex neuronal networks, and screening drugs for their effects on connectivity.
    DOI:  https://doi.org/10.1039/d4lc00107a
  26. J Cell Biol. 2024 Sep 02. pii: e202405025. [Epub ahead of print]223(9):
    ESCRT disruption provides evidence against trans-synaptic signaling via extracellular vesicles.
    Erica C Dresselhaus, Kathryn P Harris, Cassandra R Blanchette, Kate Koles, Steven J Del Signore, Matthew F Pescosolido, Biljana Ermanoska, Mark Rozencwaig, Rebecca C Soslowsky, Michael J Parisi, Bryan A Stewart, Timothy J Mosca, Avital A Rodal.
      Extracellular vesicles (EVs) are released by many cell types, including neurons, carrying cargoes involved in signaling and disease. It is unclear whether EVs promote intercellular signaling or serve primarily to dispose of unwanted materials. We show that loss of multivesicular endosome-generating endosomal sorting complex required for transport (ESCRT) machinery disrupts release of EV cargoes from Drosophila motor neurons. Surprisingly, ESCRT depletion does not affect the signaling activities of the EV cargo Synaptotagmin-4 (Syt4) and disrupts only some signaling activities of the EV cargo evenness interrupted (Evi). Thus, these cargoes may not require intercellular transfer via EVs, and instead may be conventionally secreted or function cell-autonomously in the neuron. We find that EVs are phagocytosed by glia and muscles, and that ESCRT disruption causes compensatory autophagy in presynaptic neurons, suggesting that EVs are one of several redundant mechanisms to remove cargoes from synapses. Our results suggest that synaptic EV release serves primarily as a proteostatic mechanism for certain cargoes.
    DOI:  https://doi.org/10.1083/jcb.202405025
  27. J Neurol. 2024 Jun 03.
    Long-term treatment of SOD1 ALS with tofersen: a multicentre experience in 17 patients.
    Mario Sabatelli, Federica Cerri, Riccardo Zuccarino, Agata Katia Patanella, Daniela Bernardo, Giulia Bisogni, Raffaella Tanel, Valeria Sansone, Massimiliano Filosto, Serena Lattante, Francesco Martello, Paolo Niccolò Doronzio, Salvatore Stano, Bruno Antonio Zanfini, Michela Coccia, Emanuele Maria Costantini, Andrea Lizio, Gabriele Lucioli, Alessandro Padovani, Gian Paolo Merlini, Amelia Conte.
       BACKGROUND: In Amyotrophic Lateral Sclerosis (ALS) patients with SOD1 mutation the intrathecal administration of tofersen slowed down the progression of disease in a controlled clinical study, but results were not statistically significant.
    METHODS: In this multicentre, observational study, we evaluated a cohort of 27 ALS-SOD1 patients who were treated with tofersen, focussing on 17 patients who were followed for at least 48 weeks (median period of 84 weeks, range 48-108). We compared the clinical slopes, as measured by ALSFRS-R, MRC scale and Forced Vital Capacity, during tofersen treatment with retrospective data at 1 year prior to therapy. Cerebrospinal fluid (CSF) and serum neurofilament light chains (NFL) were measured in all patients.
    RESULTS: Cumulative evaluation of the ALSFRS-R and MRC progression rates showed a statistically significant change during treatment with respect to the period prior to therapy (p = 0.023 and p = 0.007, respectively). The analysis of individual patients showed that nine of the seventeen patients substantially stabilized or slightly improved. Four patients deteriorated during treatment, while in the remaining patients the very slow course did not allow to identify significant changes. CSF and serum NFL concentration markedly decreased in the near totality of patients. Increased levels of white blood cells and proteins in the CSF were found in 60% of patients. Such alterations were clinically asymptomatic in all but two patients who showed an acute pure motor radiculitis, which responded to steroid therapy.
    CONCLUSIONS: Clinical findings and NFL analysis strongly suggest that tofersen may have a disease-modifying effect in a subset of SOD1-ALS patients.
    Keywords:  Amyotrophic lateral sclerosis; Neurofilament light chain; Oligonucleotide antisense; Tofersen
    DOI:  https://doi.org/10.1007/s00415-024-12437-7
  28. Neuron. 2024 May 31. pii: S0896-6273(24)00360-X. [Epub ahead of print]
    Cell-type-specific effects of age and sex on human cortical neurons.
    Jo-Fan Chien, Hanqing Liu, Bang-An Wang, Chongyuan Luo, Anna Bartlett, Rosa Castanon, Nicholas D Johnson, Joseph R Nery, Julia Osteen, Junhao Li, Jordan Altshul, Mia Kenworthy, Cynthia Valadon, Michelle Liem, Naomi Claffey, Caz O'Connor, Luise A Seeker, Joseph R Ecker, M Margarita Behrens, Eran A Mukamel.
      Altered transcriptional and epigenetic regulation of brain cell types may contribute to cognitive changes with advanced age. Using single-nucleus multi-omic DNA methylation and transcriptome sequencing (snmCT-seq) in frontal cortex from young adult and aged donors, we found widespread age- and sex-related variation in specific neuron types. The proportion of inhibitory SST- and VIP-expressing neurons was reduced in aged donors. Excitatory neurons had more profound age-related changes in their gene expression and DNA methylation than inhibitory cells. Hundreds of genes involved in synaptic activity, including EGR1, were less expressed in aged adults. Genes located in subtelomeric regions increased their expression with age and correlated with reduced telomere length. We further mapped cell-type-specific sex differences in gene expression and X-inactivation escape genes. Multi-omic single-nucleus epigenomes and transcriptomes provide new insight into the effects of age and sex on human neurons.
    Keywords:  DNA methylation; EGR1; X inactivation; aging; epigenome; frontal cortex; sex differences; single cell; telomere; transcriptome
    DOI:  https://doi.org/10.1016/j.neuron.2024.05.013
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