bims-axbals Biomed News
on Axonal biology and ALS
Issue of 2023–11–26
24 papers selected by
TJ Krzystek, ALS Therapy Development Institute
  1. Selective vulnerability of motor neuron types and functional groups to degeneration in amyotrophic lateral sclerosis: review of the neurobiological mechanisms and functional correlates.
  2. Role of Senataxin in Amyotrophic Lateral Sclerosis.
  3. Prognostic value of motor and extramotor involvement in ALS.
  4. Transcriptomic profiling of cerebrospinal fluid identifies ALS pathway enrichment and RNA biomarkers in MND individuals.
  5. Stress granule formation helps to mitigate neurodegeneration.
  6. Amyotrophic lateral sclerosis: exploring pathophysiology in the context of treatment.
  7. Increase in hnRNPA1 Expression Suffices to Kill Motor Neurons in Transgenic Rats.
  8. Persistent inward currents: PICking apart the temporal changes in intrinsic motor neuron excitability in amyotrophic lateral sclerosis.
  9. RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS.
  10. OPTN gene therapy increases autophagy and protects mitochondria in SOD1-G93A-expressing transgenic mice and cells.
  11. Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation.
  12. Accurate personalized survival prediction for amyotrophic lateral sclerosis patients.
  13. Lipophorin Receptors Genetically Modulate Neurodegeneration Caused by Reduction of Psn Expression in the Aging Drosophila Brain.
  14. Mutant huntingtin confers cell-autonomous phenotypes on Huntington's disease iPSC-derived microglia.
  15. ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation.
  16. Telomere shortening induces aging-associated phenotypes in hiPSC-derived neurons and astrocytes.
  17. Advances in microfluidic chips targeting toxic aggregation proteins for neurodegenerative diseases.
  18. Verbal and nonverbal fluency in amyotrophic lateral sclerosis.
  19. Real-time thiol detection in iPSC-derived neuron cultures using SemKur-IM, a novel fluorescent dithio probe.
  20. Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing.
  21. New insights into glycogen synthase kinase-3: A common target for neurodegenerative diseases.
  22. Galectin-3 aggravates microglial activation and tau transmission in tauopathy.
  23. Human neuronal maturation comes of age: cellular mechanisms and species differences.
  24. Uncovering the functional diversity of rare CRISPR-Cas systems with deep terascale clustering.
  1. Brain Struct Funct. 2023 Nov 24.
    Selective vulnerability of motor neuron types and functional groups to degeneration in amyotrophic lateral sclerosis: review of the neurobiological mechanisms and functional correlates.
    Saak V Ovsepian, Valerie B O'Leary, Salvador Martinez.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition characterised by a progressive loss of motor neurons controlling voluntary muscle activity. The disease manifests through a variety of motor dysfunctions related to the extent of damage and loss of neurons at different anatomical locations. Despite extensive research, it remains unclear why some motor neurons are especially susceptible to the disease, while others are affected less or even spared. In this article, we review the neurobiological mechanisms, neurochemical profiles, and morpho-functional characteristics of various motor neuron groups and types of motor units implicated in their differential exposure to degeneration. We discuss specific cell-autonomous (intrinsic) and extrinsic factors influencing the vulnerability gradient of motor units and motor neuron types to ALS, with their impact on disease manifestation, course, and prognosis, as revealed in preclinical and clinical studies. We consider the outstanding challenges and emerging opportunities for interpreting the phenotypic and mechanistic variability of the disease to identify targets for clinical interventions.
    Keywords:  Bulbar and spinal ALS; Excitotoxicity; Motor neuron disease; Motor units; SOD1 mutation; Skeletal and visceral muscles; TDP43
    DOI:  https://doi.org/10.1007/s00429-023-02728-6
  2. J Mol Neurosci. 2023 Nov 20.
    Role of Senataxin in Amyotrophic Lateral Sclerosis.
    Andrew Tsui, Valentina L Kouznetsova, Santosh Kesari, Milan Fiala, Igor F Tsigelny.
      Amyotrophic lateral sclerosis (ALS) is a progressive, uncurable neurodegenerative disorder characterized by the degradation of motor neurons leading to muscle impairment, failure, and death. Senataxin, encoded by the SETX gene, is a human helicase protein whose mutations have been linked with ALS onset, particularly in its juvenile ALS4 form. Using senataxin's yeast homolog Sen1 as a model for study, it is suggested that senataxin's N-terminus interacts with RNA polymerase II, whilst its C-terminus engages in helicase activity. Senataxin is heavily involved in transcription regulation, termination, and R-loop resolution, enabled by recruitment and interactions with enzymes such as ubiquitin protein ligase SAN1 and ribonuclease H (RNase H). Senataxin also engages in DNA damage response (DDR), primarily interacting with the exosome subunit Rrp45. The Sen1 mutation E1597K, alongside the L389S and R2136H gain-of-function mutations to senataxin, is shown to cause negative structural and thus functional effects to the protein, thus contributing to a disruption in WT functions, motor neuron (MN) degeneration, and the manifestation of ALS clinical symptoms. This review corroborates and summarizes published papers concerning the structure and function of senataxin as well as the effects of their mutations in ALS pathology in order to compile current knowledge and provide a reference for future research. The findings compiled in this review are indicative of the experimental and therapeutic potential of senataxin and its mutations as a target in future ALS treatment/cure discovery, with some potential therapeutic routes also being discussed in the review.
    Keywords:  Amyotrophic lateral sclerosis (ALS); Motor neurons (MNs); Sen1; Senataxin (SETX)
    DOI:  https://doi.org/10.1007/s12031-023-02169-0
  3. Amyotroph Lateral Scler Frontotemporal Degener. 2023 Nov 25. 1-8
    Prognostic value of motor and extramotor involvement in ALS.
    Vincent Kabir, Fouke Ombelet, Frederik Hobin, Nikita Lamaire, Joke De Vocht, Philip Van Damme.
      Objective: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder resulting in upper and lower motor neuron loss. ALS often has a focal onset of weakness, which subsequently spreads to other body regions. Survival is limited to two to five years after disease onset, often due to respiratory failure. Cognitive impairment is present in approximately 30% to 50% of patients and in 10%-15% of patients, the clinical criteria of frontotemporal dementia (FTD) are met. Methods: In this retrospective single-center ALS cohort study, we examined the occurrence of cognitive and behavioral impairment in relation to motor impairment at disease presentation and studied its impact on survival. Results: The degree of lower motor neuron involvement was associated with a worse survival, but there was no effect for upper motor neuron involvement. Patients who were cognitively normal had a significantly better survival compared to patients with cognitive or behavioral impairment and to patients with comorbid FTD. There was no significant difference regarding survival between patients with FTD and patients with cognitive or behavioral impairment. Conclusions: The extent of motor and extramotor involvement in patients with ALS at disease presentation holds complementary prognostic information.
    Keywords:  Amyotrophic lateral sclerosis; cognitive impairment; frontotemporal dementia; survival
    DOI:  https://doi.org/10.1080/21678421.2023.2284899
  4. Exp Biol Med (Maywood). 2023 Nov 24. 15353702231209427
    Transcriptomic profiling of cerebrospinal fluid identifies ALS pathway enrichment and RNA biomarkers in MND individuals.
    Alexander Fröhlich, Abigail L Pfaff, Vivien J Bubb, John P Quinn, Sulev Koks.
      Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder and the most common form of motor neurone disease (MND) which is characterized by the damage and death of motor neurons in the brain and spinal cord of affected individuals. Due to the heterogeneity of the disease, a better understanding of the interaction between genetics and biochemistry with the identification of biomarkers is crucial for therapy development. In this study, we used cerebrospinal fluid (CSF) RNA-sequencing data from the New York Genome Center (NYGC) ALS Consortium and analyzed differential gene expression between 47 MND individuals and 29 healthy controls. Pathway analysis showed that the affected genes are enriched in many pathways associated with ALS, including nucleocytoplasmic transport, autophagy, and apoptosis. Moreover, we assessed differential expression on both gene- and transcript-based levels and demonstrate that the expression of previously identified potential biomarkers, including CAPG, CCL3, and MAP2, was significantly higher in MND individuals. Ultimately, this study highlights the transcriptomic composition of CSF which enables insights into changes in the brain in ALS and therefore increases the confidence in the use of CSF for biomarker development.
    Keywords:  Cerebrospinal fluid; RNA-seq; amyotrophic lateral sclerosis; biomarker; motor neurone disease; transcriptome
    DOI:  https://doi.org/10.1177/15353702231209427
  5. bioRxiv. 2023 Nov 11. pii: 2023.11.07.566060. [Epub ahead of print]
    Stress granule formation helps to mitigate neurodegeneration.
    M Rebecca Glineburg, Evrim Yildirim, Nicolas Gomez, Xingli Li, Jaclyn Pak, Christopher Altheim, Jacob Waksmacki, Gerald McInerney, Sami J Barmada, Peter K Todd.
      Cellular stress pathways that inhibit translation initiation lead to transient formation of cytoplasmic RNA/protein complexes known as stress granules. Many of the proteins found within stress granules and the dynamics of stress granule formation and dissolution are implicated in neurodegenerative disease. Whether stress granule formation is protective or harmful in neurodegenerative conditions is not known. To address this, we took advantage of the alphavirus protein nsP3, which selectively binds dimers of the central stress granule nucleator protein G3BP ( rin in Drosophila ) and markedly reduces stress granule formation without directly impacting the protein translational inhibitory pathways that trigger stress granule formation. In Drosophila and rodent neurons, reducing stress granule formation with nsP3 had modest impacts on lifespan even in the setting of serial stress pathway induction. In contrast, reducing stress granule formation in models of ataxia, amyotrophic lateral sclerosis and frontotemporal dementia largely exacerbated disease phenotypes. These data support a model whereby stress granules mitigate, rather than promote, neurodegenerative cascades.
    DOI:  https://doi.org/10.1101/2023.11.07.566060
  6. Amyotroph Lateral Scler Frontotemporal Degener. 2023 Nov 24. 1-12
    Amyotrophic lateral sclerosis: exploring pathophysiology in the context of treatment.
    Angela Genge, Steven Wainwright, Christine Vande Velde.
      Amyotrophic lateral sclerosis (ALS) is a complex, neurodegenerative disorder in which alterations in structural, physiological, and metabolic parameters act synergistically. Over the last decade there has been a considerable focus on developing drugs to slow the progression of the disease. Despite this, only four disease-modifying therapies are approved in North America. Although additional research is required for a thorough understanding of ALS, we have accumulated a large amount of knowledge that could be better integrated into future clinical trials to accelerate drug development and provide patients with improved treatment options. It is likely that future, successful ALS treatments will take a multi-pronged therapeutic approach, targeting different pathways, akin to personalized medicine in oncology. In this review, we discuss the link between ALS pathophysiology and treatments, looking at the therapeutic failures as learning opportunities that can help us refine and optimize drug development.
    Keywords:  Genetics; glutamate excitotoxicity; mitochondria; oxidative stress; therapeutics
    DOI:  https://doi.org/10.1080/21678421.2023.2278503
  7. Int J Mol Sci. 2023 Nov 11. pii: 16214. [Epub ahead of print]24(22):
    Increase in hnRNPA1 Expression Suffices to Kill Motor Neurons in Transgenic Rats.
    Bo Huang, Xionghao Liu, Tingting Zhang, Qinxue Wu, Cao Huang, Xu-Gang Xia, Hongxia Zhou.
      A dominant mutation in hnRNPA1 causes amyotrophic lateral sclerosis (ALS), but it is not known whether this mutation leads to motor neuron death through increased or decreased function. To elucidate the relationship between pathogenic hnRNPA1 mutation and its native function, we created novel transgenic rats that overexpressed wildtype rat hnRNPA1 exclusively in motor neurons. This targeted expression of wildtype hnRNPA1 caused severe motor neuron loss and subsequent denervation muscle atrophy in transgenic rats that recapitulated the characteristics of ALS. These findings demonstrate that the augmentation of hnRNPA1 expression suffices to trigger motor neuron degeneration and the manifestation of ALS-like phenotypes. It is reasonable to infer that an amplification of an as-yet undetermined hnRNPA1 function plays a pivotal role in the pathogenesis of familial ALS caused by pathogenic hnRNPA1 mutation.
    Keywords:  ALS; hnRNPA1; motor neuron disease; rats; transgenic rodents
    DOI:  https://doi.org/10.3390/ijms242216214
  8. J Physiol. 2023 Nov 20.
    Persistent inward currents: PICking apart the temporal changes in intrinsic motor neuron excitability in amyotrophic lateral sclerosis.
    Aoife D Slyne, Seán C Ó Murchú.
      
    Keywords:  amyotrophic lateral sclerosis; hyperexcitability; motor neuron; persistent inward currents
    DOI:  https://doi.org/10.1113/JP285776
  9. Sci Adv. 2023 11 24. 9(47): eadg3193
    RGMa collapses the neuronal actin barrier against disease-implicated protein and exacerbates ALS.
    Mikito Shimizu, Naoyuki Shiraishi, Satoru Tada, Tsutomu Sasaki, Goichi Beck, Seiichi Nagano, Makoto Kinoshita, Hisae Sumi, Tomoyuki Sugimoto, Yoko Ishida, Toru Koda, Teruyuki Ishikura, Yasuko Sugiyama, Keigo Kihara, Minami Kanakura, Tsuneo Nakajima, Shuko Takeda, Masanori P Takahashi, Toshihide Yamashita, Tatsusada Okuno, Hideki Mochizuki.
      Repulsive guidance molecule A (RGMa) was originally identified as a neuronal growth cone-collapsing factor. Previous reports have demonstrated the multifunctional roles of RGMa mediated by neogenin1. However, the pathogenic involvement of RGMa in amyotrophic lateral sclerosis (ALS) remains unclear. Here, we demonstrated that RGMa concentration was elevated in the cerebrospinal fluid of both patients with ALS and transgenic mice overexpressing the mutant human superoxide dismutase1 (mSOD1 mice). Treatment with humanized anti-RGMa monoclonal antibody ameliorated the clinical symptoms in mSOD1 mice. Histochemical analysis revealed that the anti-RGMa antibody significantly decreased mutant SOD1 protein accumulation in the motor neurons of mSOD1 mice via inhibition of actin depolymerization. In vitro analysis revealed that the anti-RGMa antibody inhibited the cellular uptake of the mutant SOD1 protein, presumably by reinforcing the neuronal actin barrier. Collectively, these data suggest that RGMa leads to the collapse of the neuronal actin barrier and promotes aberrant protein deposition, resulting in exacerbation of the ALS pathology.
    DOI:  https://doi.org/10.1126/sciadv.adg3193
  10. FEBS J. 2023 Nov 20.
    OPTN gene therapy increases autophagy and protects mitochondria in SOD1-G93A-expressing transgenic mice and cells.
    Di Wen, Yingxiao Ji, Yuanyuan Li, Weisong Duan, Yanyan Wang, Zhongyao Li, Meichun Tao, Yakun Liu.
      Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor neuron (MN) death. Mutation of the superoxide dismutase 1 (SOD1) gene, which results in abnormal protein aggregation, is one of the causes of familial ALS. Autophagic dysfunction occurs in SOD1-G93A mutant mice as the disease progresses, but the aetiology of this disease is still unclear. Optineurin (OPTN) is an adaptor that is involved in autophagy and participates in aggrephagy and mitophagy. Previous studies have established that OPTN mutations contribute to diseases such as glaucoma and ALS. However, the function of OPTN in autophagy and mitophagy has not been intensively investigated in models of ALS. In this study, we assessed the beneficial effect of OPTN on autophagy and mitochondrial function by intrathecally injecting adeno-associated virus 9 (AAV9)-OPTN into SOD1-G93A transgenic mice, and by administering lentivirus (LV)-OPTN to cells expressing the SOD1-G93A mutant protein. The expression of voltage dependent anion channel 1 (VDAC1) was increased and autophagy was elevated after OPTN gene therapy, as shown by a lower level of p62 and a higher level of microtubule-associated protein 1A/1B-light chain 3 (LC3)-II. Moreover, using electron microscopy, we observed a hyperpolarized mitochondrial transmembrane potential and reversal of mitochondrial morphological abnormalities. Furthermore, the protein level of TANK-binding kinase 1 (TBK1) was increased, suggesting that mitophagy was increased. Our findings from both animal and cell line studies strongly suggest that OPTN gene therapy is a powerful strategy to increase autophagy and protect mitochondria to prevent the progression of ALS, and could be effective in the treatment of ALS.
    Keywords:  MMP; OPTN; SOD1-G93A transgenic mice; amyotrophic lateral sclerosis; autophagy pathway
    DOI:  https://doi.org/10.1111/febs.17009
  11. Nat Neurosci. 2023 Nov 23.
    Stathmin-2 loss leads to neurofilament-dependent axonal collapse driving motor and sensory denervation.
    Jone López-Erauskin, Mariana Bravo-Hernandez, Maximiliano Presa, Michael W Baughn, Ze'ev Melamed, Melinda S Beccari, Ana Rita Agra de Almeida Quadros, Olatz Arnold-Garcia, Aamir Zuberi, Karen Ling, Oleksandr Platoshyn, Elkin Niño-Jara, I Sandra Ndayambaje, Melissa McAlonis-Downes, Larissa Cabrera, Jonathan W Artates, Jennifer Ryan, Anita Hermann, John Ravits, C Frank Bennett, Paymaan Jafar-Nejad, Frank Rigo, Martin Marsala, Cathleen M Lutz, Don W Cleveland, Clotilde Lagier-Tourenne.
      The mRNA transcript of the human STMN2 gene, encoding for stathmin-2 protein (also called SCG10), is profoundly impacted by TAR DNA-binding protein 43 (TDP-43) loss of function. The latter is a hallmark of several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Using a combination of approaches, including transient antisense oligonucleotide-mediated suppression, sustained shRNA-induced depletion in aging mice, and germline deletion, we show that stathmin-2 has an important role in the establishment and maintenance of neurofilament-dependent axoplasmic organization that is critical for preserving the caliber and conduction velocity of myelinated large-diameter axons. Persistent stathmin-2 loss in adult mice results in pathologies found in ALS, including reduced interneurofilament spacing, axonal caliber collapse that drives tearing within outer myelin layers, diminished conduction velocity, progressive motor and sensory deficits, and muscle denervation. These findings reinforce restoration of stathmin-2 as an attractive therapeutic approach for ALS and other TDP-43-dependent neurodegenerative diseases.
    DOI:  https://doi.org/10.1038/s41593-023-01496-0
  12. Sci Rep. 2023 Nov 24. 13(1): 20713
    Accurate personalized survival prediction for amyotrophic lateral sclerosis patients.
    Li-Hao Kuan, Pedram Parnianpour, Rafsanjany Kushol, Neeraj Kumar, Tanushka Anand, Sanjay Kalra, Russell Greiner.
      Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive neurodegenerative disease. Accurately predicting the survival time for ALS patients can help patients and clinicians to plan for future treatment and care. We describe the application of a machine-learned tool that incorporates clinical features and cortical thickness from brain magnetic resonance (MR) images to estimate the time until a composite respiratory failure event for ALS patients, and presents the prediction as individual survival distributions (ISDs). These ISDs provide the probability of survival (none of the respiratory failures) at multiple future time points, for each individual patient. Our learner considers several survival prediction models, and selects the best model to provide predictions. We evaluate our learned model using the mean absolute error margin (MAE-margin), a modified version of mean absolute error that handles data with censored outcomes. We show that our tool can provide helpful information for patients and clinicians in planning future treatment.
    DOI:  https://doi.org/10.1038/s41598-023-47935-7
  13. Genetics. 2023 Nov 23. pii: iyad202. [Epub ahead of print]
    Lipophorin Receptors Genetically Modulate Neurodegeneration Caused by Reduction of Psn Expression in the Aging Drosophila Brain.
    Jongkyun Kang, Chen Zhang, Yuhao Wang, Jian Feng, Bonnie Berger, Norbert Perrimon, Jie Shen.
      Mutations in the Presenilin (PSEN) genes are the most common cause of early-onset familial Alzheimer's disease (FAD). Studies in cell culture, in vitro biochemical systems, and knockin mice showed that PSEN mutations are loss-of-function mutations, impairing γ-secretase activity. Mouse genetic analysis highlighted the importance of Presenilin (PS) in learning and memory, synaptic plasticity and neurotransmitter release, and neuronal survival, and Drosophila studies further demonstrated an evolutionarily conserved role of PS in neuronal survival during aging. However, molecular pathways that interact with PS in neuronal survival remain unclear. To identify genetic modifiers that modulate PS-dependent neuronal survival, we developed a new Drosophila Psn model that exhibits age-dependent neurodegeneration and increases of apoptosis. Following a bioinformatic analysis, we tested top ranked candidate genes by selective knockdown (KD) of each gene in neurons using two independent RNAi lines in Psn KD models. Interestingly, 4 of the 9 genes enhancing neurodegeneration in Psn KD flies are involved in lipid transport and metabolism. Specifically, neuron-specific KD of lipophorin receptors, lpr1 and lpr2, dramatically worsens neurodegeneration in Psn KD flies, and overexpression of lpr1 or lpr2 does not alleviate Psn KD-induced neurodegeneration. Furthermore, lpr1 or lpr2 KD alone also leads to neurodegeneration, increased apoptosis, climbing defects, and shortened lifespan. Lastly, heterozygotic deletions of lpr1 and lpr2 or homozygotic deletions of lpr1 or lpr2 similarly lead to age-dependent neurodegeneration and further exacerbate neurodegeneration in Psn KD flies. These findings show that LpRs modulate Psn-dependent neuronal survival and are critically important for neuronal integrity in the aging brain.
    Keywords:  Alzheimer’s disease; Presenilin; genetic modifier; lipid transport and metabolism; lipoproteins
    DOI:  https://doi.org/10.1093/genetics/iyad202
  14. Sci Rep. 2023 Nov 22. 13(1): 20477
    Mutant huntingtin confers cell-autonomous phenotypes on Huntington's disease iPSC-derived microglia.
    Nina Stöberl, Jasmine Donaldson, Caroline S Binda, Branduff McAllister, Hazel Hall-Roberts, Lesley Jones, Thomas H Massey, Nicholas D Allen.
      Huntington's disease (HD) is a neurodegenerative disorder caused by a dominantly inherited CAG repeat expansion in the huntingtin gene (HTT). Neuroinflammation and microglia have been implicated in HD pathology, however it has been unclear if mutant HTT (mHTT) expression has an adverse cell-autonomous effect on microglial function, or if they are only activated in response to the neurodegenerative brain environment in HD. To establish a human cell model of HD microglia function, we generated isogenic controls for HD patient-derived induced pluripotent stem cells (iPSC) with 109 CAG repeats (Q109). Q109 and isogenic Q22 iPSC, as well as non-isogenic Q60 and Q33 iPSC lines, were differentiated to iPSC-microglia. Our study supports a model of basal microglia dysfunction in HD leading to elevated pro-inflammatory cytokine production together with impaired phagocytosis and endocytosis capacity, in the absence of immune stimulation. These findings are consistent with early microglia activation observed in pre-manifest patients and indicate that mHTT gene expression affects microglia function in a cell-autonomous way.
    DOI:  https://doi.org/10.1038/s41598-023-46852-z
  15. Sci Rep. 2023 Nov 22. 13(1): 20467
    ALS/FTD-associated mutation in cyclin F inhibits ER-Golgi trafficking, inducing ER stress, ERAD and Golgi fragmentation.
    Audrey M G Ragagnin, Vinod Sundaramoorthy, Fabiha Farzana, Shashi Gautam, Sayanthooran Saravanabavan, Zeinab Takalloo, Prachi Mehta, Dzung Do-Ha, Sonam Parakh, Sina Shadfar, Julie Hunter, Marta Vidal, Cyril J Jagaraj, Mariana Brocardo, Anna Konopka, Shu Yang, Stephanie L Rayner, Kelly L Williams, Ian P Blair, Roger S Chung, Albert Lee, Lezanne Ooi, Julie D Atkin.
      Amyotrophic lateral sclerosis (ALS) is a severely debilitating neurodegenerative condition that is part of the same disease spectrum as frontotemporal dementia (FTD). Mutations in the CCNF gene, encoding cyclin F, are present in both sporadic and familial ALS and FTD. However, the pathophysiological mechanisms underlying neurodegeneration remain unclear. Proper functioning of the endoplasmic reticulum (ER) and Golgi apparatus compartments is essential for normal physiological activities and to maintain cellular viability. Here, we demonstrate that ALS/FTD-associated variant cyclin FS621G inhibits secretory protein transport from the ER to Golgi apparatus, by a mechanism involving dysregulation of COPII vesicles at ER exit sites. Consistent with this finding, cyclin FS621G also induces fragmentation of the Golgi apparatus and activates ER stress, ER-associated degradation, and apoptosis. Induction of Golgi fragmentation and ER stress were confirmed with a second ALS/FTD variant cyclin FS195R, and in cortical primary neurons. Hence, this study provides novel insights into pathogenic mechanisms associated with ALS/FTD-variant cyclin F, involving perturbations to both secretory protein trafficking and ER-Golgi homeostasis.
    DOI:  https://doi.org/10.1038/s41598-023-46802-9
  16. Biogerontology. 2023 Nov 21.
    Telomere shortening induces aging-associated phenotypes in hiPSC-derived neurons and astrocytes.
    Jasmine Harley, Munirah Mohamad Santosa, Chong Yi Ng, Oleg V Grinchuk, Jin-Hui Hor, Yajing Liang, Valerie Jingwen Lim, Wee Wei Tee, Derrick Sek Tong Ong, Shi-Yan Ng.
      Telomere shortening is a well-established hallmark of cellular aging. Telomerase reverse transcriptase (TERT) plays a crucial role in maintaining the length of telomeres, which are specialised protective caps at the end of chromosomes. The lack of in vitro aging models, particularly for the central nervous system (CNS), has impeded progress in understanding aging and age-associated neurodegenerative diseases. In this study, we aimed to explore the possibility of inducing aging-associated features in cell types of the CNS using hiPSC (human induced pluripotent stem cell) technology. To achieve this, we utilised CRISPR/Cas9 to generate hiPSCs with a loss of telomerase function and shortened telomeres. Through directed differentiation, we generated motor neurons and astrocytes to investigate whether telomere shortening could lead to age-associated phenotypes. Our findings revealed that shortened telomeres induced age-associated characteristics in both motor neurons and astrocytes including increased cellular senescence, heightened inflammation, and elevated DNA damage. We also observed cell-type specific age-related morphology changes. Additionally, our study highlighted the fundamental role of TERT and telomere shortening in neural progenitor cell (NPC) proliferation and neuronal differentiation. This study serves as a proof of concept that telomere shortening can effectively induce aging-associated phenotypes, thereby providing a valuable tool to investigate age-related decline and neurodegenerative diseases.
    Keywords:  Aging; Astrocytes; Neurons; Telomerase reverse transcriptase; Telomeres; hiPSC
    DOI:  https://doi.org/10.1007/s10522-023-10076-5
  17. Int J Biol Macromol. 2023 Nov 20. pii: S0141-8130(23)05207-8. [Epub ahead of print] 128308
    Advances in microfluidic chips targeting toxic aggregation proteins for neurodegenerative diseases.
    Liang Li, Tong Lei, Cencan Xing, Hongwu Du.
      Neurodegenerative diseases (NDs) are characterized by nervous system damage, often influenced by genetic and aging factors. Pathological analysis frequently reveals the presence of aggregated toxic proteins. The intricate and poorly understood origins of these diseases have hindered progress in early diagnosis and drug development. The development of novel in-vitro and in-vivo models could enhance our comprehension of ND mechanisms and facilitate clinical treatment advancements. Microfluidic chips are employed to establish three-dimensional culture conditions, replicating the human ecological niche and creating a microenvironment conducive to neuronal cell survival. The incorporation of mechatronic controls unifies the chip, cells, and culture medium optimizing living conditions for the cells. This study provides a comprehensive overview of microfluidic chip applications in drug and biomarker screening for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, and amyotrophic lateral sclerosis. Our Lab-on-a-Chip system releases toxic proteins to simulate the pathological characteristics of neurodegenerative diseases, encompassing β-amyloid, α-synuclein, huntingtin, TAR DNA-binding protein 43, and Myelin Basic Protein. Investigating molecular and cellular interactions in vitro can enhance our understanding of disease mechanisms while minimizing harmful protein levels and can aid in screening potential therapeutic agents. We anticipate that our research will promote the utilization of microfluidic chips in both fundamental research and clinical applications for neurodegenerative diseases.
    Keywords:  Biomarkers; Drugs; Microfluidic chip; Model; Neurodegenerative diseases
    DOI:  https://doi.org/10.1016/j.ijbiomac.2023.128308
  18. J Neuropsychol. 2023 Nov 23.
    Verbal and nonverbal fluency in amyotrophic lateral sclerosis.
    Megan S Barker, Amelia Ceslis, Rosemary Argall, Pamela McCombe, Robert D Henderson, Gail A Robinson.
      Amyotrophic lateral sclerosis (ALS) is a multi-system disorder that commonly affects cognition and behaviour. Verbal fluency impairments are consistently reported in ALS patients, and we aimed to investigate whether this deficit extends beyond the verbal domain. We further aimed to determine whether deficits are underpinned by a primary intrinsic response generation impairment (i.e., a global reduction across tasks), potentially related to apathy, or an inability to maintain responding over time (i.e., a 'drop off' pattern). Twenty-two ALS patients and 21 demographically-matched controls completed verbal and nonverbal fluency tasks (phonemic/semantic word fluency, design fluency, gesture fluency and ideational fluency), requiring the generation of responses over a specified time period. Fluency performance was analysed in terms of the overall number of novel items produced, as well as the number of items produced in the first 'initiation' and the remaining 'maintenance' time periods. ALS patients' overall performance was not globally reduced across tasks. Patients were impaired only on meaningful gesture fluency, which requires the generation of gestures that communicate meaning (e.g., waving). On phonemic fluency, ALS patients showed a 'drop off' pattern of performance, where they had difficulty maintaining responding over time, but this pattern was not evident on the other fluency tasks. Apathy did not appear to be related to fluency performance. The selective meaningful gesture fluency deficit, in the context of preserved meaningless gesture fluency, highlights that the retrieval of action knowledge may be weakened in early ALS.
    Keywords:  action semantics; amyotrophic lateral sclerosis; nonverbal fluency; verbal fluency
    DOI:  https://doi.org/10.1111/jnp.12354
  19. SLAS Discov. 2023 Nov 20. pii: S2472-5552(23)00081-3. [Epub ahead of print]
    Real-time thiol detection in iPSC-derived neuron cultures using SemKur-IM, a novel fluorescent dithio probe.
    Roxanne Alvarez, Jayson Kurfis, Michael Hendrickson, Daniel S Sem.
      Neurological disorders associated with inflammation and oxidative stress show reduced glutathione (GSH) levels in the human brain. Drug discovery efforts and pharmacological studies would benefit from tools (e.g. chemical probes) that detect changes to oxidative stress, from the perspective of physiologically-relevant reporters like cellular thiols, including GSH. To this end, we have developed a fluorescence visualization assay using iPSC-derived cortical glutamatergic neurons that were loaded with 25 μM of a novel thiol-detection fluorescent probe, SemKur-IM. This probe enables visualization of cellular thiol level changes in the neuronal somas and neurites, in response exposure to N-acetyl-cysteine (NAC). Cellular thiol redox state was observed to change, based on an increase in green fluorescence (485 nm excitation maximum; 525 nm emission maximum) due to changes in thiol levels, from 0 to 40 mM. Interestingly, prior to treatment with NAC, cells did not appear to have significant levels of reduced thiols. Our studies demonstrate the utility of SemKur-IM in the detection of thiol levels in live cells in response to chemical exposures, such as from drugs that return the cell to a healthier reduced state. An initial application to screening the effects of an Alzheimer's disease drug candidate, Posiphen, using fluorescence cell sorting is presented. Other potential applications include high throughput screening of central nervous system (CNS) drugs thought to work by affecting cellular redox state in neurons.
    Keywords:  Disulfide; Drug discovery; Neurons; Oxidative stress; Thiol; iPSC
    DOI:  https://doi.org/10.1016/j.slasd.2023.11.003
  20. Nat Commun. 2023 Nov 21. 14(1): 7575
    Small molecule regulators of microRNAs identified by high-throughput screen coupled with high-throughput sequencing.
    Lien D Nguyen, Zhiyun Wei, M Catarina Silva, Sergio Barberán-Soler, Jiarui Zhang, Rosalia Rabinovsky, Christina R Muratore, Jonathan M S Stricker, Colin Hortman, Tracy L Young-Pearse, Stephen J Haggarty, Anna M Krichevsky.
      MicroRNAs (miRNAs) regulate fundamental biological processes by silencing mRNA targets and are dysregulated in many diseases. Therefore, miRNA replacement or inhibition can be harnessed as potential therapeutics. However, existing strategies for miRNA modulation using oligonucleotides and gene therapies are challenging, especially for neurological diseases, and none have yet gained clinical approval. We explore a different approach by screening a biodiverse library of small molecule compounds for their ability to modulate hundreds of miRNAs in human induced pluripotent stem cell-derived neurons. We demonstrate the utility of the screen by identifying cardiac glycosides as potent inducers of miR-132, a key neuroprotective miRNA downregulated in Alzheimer's disease and other tauopathies. Coordinately, cardiac glycosides downregulate known miR-132 targets, including Tau, and protect rodent and human neurons against various toxic insults. More generally, our dataset of 1370 drug-like compounds and their effects on the miRNome provides a valuable resource for further miRNA-based drug discovery.
    DOI:  https://doi.org/10.1038/s41467-023-43293-0
  21. Biochem Pharmacol. 2023 Nov 18. pii: S0006-2952(23)00516-6. [Epub ahead of print]218 115923
    New insights into glycogen synthase kinase-3: A common target for neurodegenerative diseases.
    Chengfeng Wang, Yu Cui, Tong Xu, Yu Zhou, Rong Yang, Ting Wang.
      Glycogen synthase kinase 3 (GSK-3) is a highly conserved protein serine/threonine kinase that plays a central role in a wide variety of cellular processes to coordinate catabolic and anabolic pathways and regulate cell growth and fate. There is increasing evidence showing that abnormal glycogen synthase kinase 3 (GSK-3) is associated with the pathogenesis and progression of many disorders, such as cancer, diabetes, psychiatric diseases, and neurodegenerative diseases. In this review, we summarize recent findings about the regulatory role of GSK-3 in the occurrence and development of multiple neurodegenerative diseases, mainly focusing on Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. The aim of this study is to provide new insight into the shared working mechanism of GSK-3 as a therapeutic target of multiple neurodegenerative diseases.
    Keywords:  GSK-3; GSK-3 inhibitors; Neurodegeneration; Neuroprotection; Phosphorylation
    DOI:  https://doi.org/10.1016/j.bcp.2023.115923
  22. J Clin Invest. 2023 Nov 21. pii: e165523. [Epub ahead of print]
    Galectin-3 aggravates microglial activation and tau transmission in tauopathy.
    Jian Jing Siew, Hui-Mei Chen, Feng-Lan Chiu, Chia-Wei Lee, Yao-Ming Chang, Hung-Lin Chen, Thi Ngoc Anh Nguyen, Hung-Ting Liao, Mengyu Liu, Hsiao-Tien Hagar, Yung-Chen Sun, Hsing-Lin Lai, Min-Hao Kuo, David Blum, Luc Buée, Lee-Way Jin, Shih-Yu Chen, Tai-Ming Ko, Jie-Rong Huang, Hung-Chih Kuo, Fu-Tong Liu, Yijuang Chern.
      Alzheimer's disease (AD) is characterized by the accumulation of amyloid-β plaques, aggregation of hyperphosphorylated tau (pTau), and microglia activation. Galectin-3 (Gal3) is a β-galactoside-binding protein that has been implicated in amyloid pathology. Its role in tauopathy remains enigmatic. Here, we showed that Gal3 was upregulated in the microglia of humans and mice with tauopathy. pTau triggered the release of Gal3 from human induced pluripotent stem cell-derived microglia (iMGL) in both its free and extracellular vesicular (EV)-associated forms. Both forms of Gal3 increased the accumulation of pathogenic tau in recipient cells. Binding of Gal3 to pTau greatly enhanced tau fibrillation. Besides Gal3, pTau was sorted into EVs for transmission. Moreover, pTau markedly enhanced the numbers of EVs released by iMGL in a Gal3-dependent manner, suggesting a role of Gal3 in EVs biogenesis. Single-cell RNA-seq analysis of the hippocampus of a mouse model of tauopathy (THY-Tau22) revealed a group of pathogenic tau-evoked, Gal3-associated microglia (GAM) with altered cellular machineries implicated in neurodegeneration, including enhanced immune and inflammatory responses. Genetic removal of Gal3 in THY-Tau22 mice suppressed microglia activation, reduced the level of pTau and synaptic loss in neurons, and rescued the memory impairment. Collectively, Gal3 is a potential therapeutic target for tauopathy.
    Keywords:  Alzheimer disease; Neurodegeneration; Neuroscience; iPS cells
    DOI:  https://doi.org/10.1172/JCI165523
  23. Nat Rev Neurosci. 2023 Nov 23.
    Human neuronal maturation comes of age: cellular mechanisms and species differences.
    Jenelle L Wallace, Alex A Pollen.
      The delayed and prolonged postmitotic maturation of human neurons, compared with neurons from other species, may contribute to human-specific cognitive abilities and neurological disorders. Here we review the mechanisms of neuronal maturation, applying lessons from model systems to understand the specific features of protracted human cortical maturation and species differences. We cover cell-intrinsic features of neuronal maturation, including transcriptional, epigenetic and metabolic mechanisms, as well as cell-extrinsic features, including the roles of activity and synapses, the actions of glial cells and the contribution of the extracellular matrix. We discuss evidence for species differences in biochemical reaction rates, the proposed existence of an epigenetic maturation clock and the contributions of both general and modular mechanisms to species-specific maturation timing. Finally, we suggest approaches to measure, improve and accelerate the maturation of human neurons in culture, examine crosstalk and interactions among these different aspects of maturation and propose conceptual models to guide future studies.
    DOI:  https://doi.org/10.1038/s41583-023-00760-3
  24. Science. 2023 Nov 24. 382(6673): eadi1910
    Uncovering the functional diversity of rare CRISPR-Cas systems with deep terascale clustering.
    Han Altae-Tran, Soumya Kannan, Anthony J Suberski, Kepler S Mears, F Esra Demircioglu, Lukas Moeller, Selin Kocalar, Rachel Oshiro, Kira S Makarova, Rhiannon K Macrae, Eugene V Koonin, Feng Zhang.
      Microbial systems underpin many biotechnologies, including CRISPR, but the exponential growth of sequence databases makes it difficult to find previously unidentified systems. In this work, we develop the fast locality-sensitive hashing-based clustering (FLSHclust) algorithm, which performs deep clustering on massive datasets in linearithmic time. We incorporated FLSHclust into a CRISPR discovery pipeline and identified 188 previously unreported CRISPR-linked gene modules, revealing many additional biochemical functions coupled to adaptive immunity. We experimentally characterized three HNH nuclease-containing CRISPR systems, including the first type IV system with a specified interference mechanism, and engineered them for genome editing. We also identified and characterized a candidate type VII system, which we show acts on RNA. This work opens new avenues for harnessing CRISPR and for the broader exploration of the vast functional diversity of microbial proteins.
    DOI:  https://doi.org/10.1126/science.adi1910
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