bims-axbals Biomed News
on Axonal biology and ALS
Issue of 2024–08–25
twenty papers selected by
TJ Krzystek, ALS Therapy Development Institute
  1. LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.
  2. The prion-like effect and prion-like protein targeting strategy in amyotrophic lateral sclerosis.
  3. Cyclase-associated protein (CAP) inhibits inverted formin 2 (INF2) to induce dendritic spine maturation.
  4. ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes.
  5. Diverse Phenotypic Presentation of the Welander Distal Myopathy Founder Mutation, With Myopathy and Amyotrophic Lateral Sclerosis in the Same Family.
  6. VPS35 or retromer as a potential target for neurodegenerative disorders: barriers to progress.
  7. Phosphoglycerate kinase is a central leverage point in Parkinson's disease-driven neuronal metabolic deficits.
  8. Recent advances and applications of human brain models.
  9. Artificial targeting of autophagy components to mitochondria reveals both conventional and unconventional mitophagy pathways.
  10. Synaptic gene expression changes in frontotemporal dementia due to the MAPT 10 + 16 mutation.
  11. Quercetin induces a slow myofiber phenotype in engineered human skeletal muscle tissues.
  12. Toward the latest advancements in cardiac regeneration using induced pluripotent stem cells (iPSCs) technology: approaches and challenges.
  13. Amyotrophic Lateral Sclerosis (ALS): An Overview of Genetic and Metabolic Signaling Mechanisms.
  14. The ALS-associated KIF5A P986L variant is not pathogenic for Drosophila motoneurons.
  15. RXR nuclear receptor signaling modulates lipid metabolism and triggers lysosomal clearance of alpha-synuclein in neuronal models of synucleinopathy.
  16. Motion blur microscopy: in vitro imaging of cell adhesion dynamics in whole blood flow.
  17. Coffee and amyotrophic lateral sclerosis (ALS).
  18. The actin-spectrin submembrane scaffold restricts endocytosis along proximal axons.
  19. Peripheral sequestration of huntingtin delays neuronal death and depends on N-terminal ubiquitination.
  20. A guide to selecting high-performing antibodies for Synaptotagmin-1 (Uniprot ID P21579) for use in western blot, immunoprecipitation, immunofluorescence and flow cytometry.
  1. Trends Mol Med. 2024 Aug 16. pii: S1471-4914(24)00189-8. [Epub ahead of print]
    LRRK2 in Parkinson's disease: upstream regulation and therapeutic targeting.
    Yulan Xiong, Jianzhong Yu.
      Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common causes of Parkinson's disease (PD) to date. Dysfunction in LRRK2 enzymatic activities and elevated protein levels are associated with the disease. How is LRRK2 activated, and what downstream molecular and cellular processes does LRRK2 regulate? Addressing these questions is crucial to decipher the disease mechanisms. In this review we focus on the upstream regulations and briefly discuss downstream substrates of LRRK2 as well as the cellular consequences caused by these regulations. Building on these basic findings, we discuss therapeutic strategies targeting LRRK2 and highlight the challenges in clinical trials. We further highlight the important questions that remains to be answered in the LRRK2 field.
    Keywords:  LRRK2; Parkinson's disease; disease mechanisms; leucine-rich repeat kinase 2; therapeutic targets; upstream regulation
    DOI:  https://doi.org/10.1016/j.molmed.2024.07.003
  2. Heliyon. 2024 Aug 15. 10(15): e34963
    The prion-like effect and prion-like protein targeting strategy in amyotrophic lateral sclerosis.
    Yang Wenzhi, Liu Xiangyi, Fan Dongsheng.
      Pathological proteins in amyotrophic lateral sclerosis (ALS), such as superoxide dismutase 1, TAR DNA-binding protein 43, and fused in sarcoma, exhibit a prion-like pattern. All these proteins have a low-complexity domain and seeding activity in cells. In this review, we summarize the studies on the prion-like effect of these proteins and list six prion-like protein targeting strategies that we believe have potential for ALS therapy, including antisense oligonucleotides, antibody-based technology, peptide, protein chaperone, autophagy enhancement, and heteromultivalent compounds. Considering the pathological complexity and heterogeneity of ALS, we believe that the final solution to ALS therapy is most likely to be an individualized cocktail therapy, including clearance of toxicity, blockage of pathological progress, and protection of neurons.
    Keywords:  ALS; Prion-like; Protein
    DOI:  https://doi.org/10.1016/j.heliyon.2024.e34963
  3. Cell Mol Life Sci. 2024 Aug 18. 81(1): 353
    Cyclase-associated protein (CAP) inhibits inverted formin 2 (INF2) to induce dendritic spine maturation.
    Cara Schuldt, Sharof Khudayberdiev, Ben-David Chandra, Uwe Linne, Marco B Rust.
      The morphology of dendritic spines, the postsynaptic compartment of most excitatory synapses, decisively modulates the function of neuronal circuits as also evident from human brain disorders associated with altered spine density or morphology. Actin filaments (F-actin) form the backbone of spines, and a number of actin-binding proteins (ABP) have been implicated in shaping the cytoskeleton in mature spines. Instead, only little is known about the mechanisms that control the reorganization from unbranched F-actin of immature spines to the complex, highly branched cytoskeleton of mature spines. Here, we demonstrate impaired spine maturation in hippocampal neurons upon genetic inactivation of cyclase-associated protein 1 (CAP1) and CAP2, but not of CAP1 or CAP2 alone. We found a similar spine maturation defect upon overactivation of inverted formin 2 (INF2), a nucleator of unbranched F-actin with hitherto unknown synaptic function. While INF2 overactivation failed in altering spine density or morphology in CAP-deficient neurons, INF2 inactivation largely rescued their spine defects. From our data we conclude that CAPs inhibit INF2 to induce spine maturation. Since we previously showed that CAPs promote cofilin1-mediated cytoskeletal remodeling in mature spines, we identified them as a molecular switch that control transition from filopodia-like to mature spines.
    Keywords:  Acetylated actin; Actin acetylation; Spinogenesis; Synapse formation; Synaptogenesis
    DOI:  https://doi.org/10.1007/s00018-024-05393-y
  4. Cell Rep. 2024 Aug 19. pii: S2211-1247(24)00976-8. [Epub ahead of print]43(8): 114626
    ALS-FUS mutations cause abnormal PARylation and histone H1.2 interaction, leading to pathological changes.
    Hafiza Alirzayeva, Rute Loureiro, Seda Koyuncu, Franziska Hommen, Yara Nabawi, William Hongyu Zhang, Thien T P Dao, Markus Wehrmann, Hyun Ju Lee, David Vilchez.
      The majority of severe early-onset and juvenile cases of amyotrophic lateral sclerosis (ALS) are caused by mutations in the FUS gene, resulting in rapid disease progression. Mutant FUS accumulates within stress granules (SGs), thereby affecting the dynamics of these ribonucleoprotein complexes. Here, we define the interactome of the severe mutant FUSP525L variant in human induced pluripotent stem cell (iPSC)-derived motor neurons. We find increased interaction of FUSP525L with the PARP1 enzyme, promoting poly-ADP-ribosylation (PARylation) and binding of FUS to histone H1.2. Inhibiting PARylation or reducing H1.2 levels alleviates mutant FUS aggregation, SG alterations, and apoptosis in human motor neurons. Conversely, elevated H1.2 levels exacerbate FUS-ALS phenotypes, driven by the internally disordered terminal domains of H1.2. In C. elegans models, knockdown of H1.2 and PARP1 orthologs also decreases FUSP525L aggregation and neurodegeneration, whereas H1.2 overexpression worsens ALS-related changes. Our findings indicate a link between PARylation, H1.2, and FUS with potential therapeutic implications.
    Keywords:  CP: Cell biology; FUS; PARP1; PARylation; amyotrophic lateral sclerosis; histone H1.2; neurodegeneration; protein aggregation; proteostasis; stress granules
    DOI:  https://doi.org/10.1016/j.celrep.2024.114626
  5. J Clin Neuromuscul Dis. 2024 Sep 01. 26(1): 42-46
    Diverse Phenotypic Presentation of the Welander Distal Myopathy Founder Mutation, With Myopathy and Amyotrophic Lateral Sclerosis in the Same Family.
    Nicholas Purcell, Georgios Manousakis.
       ABSTRACT: Welander distal myopathy is a rare myopathy with prominent and early involvement of distal upper extremity muscles, prevalent in individuals of Scandinavian origin, and caused by a founder mutation in the cytotoxic granule-associated RNA-binding protein (T-cell intracellular antigen-1; TIA1), E384K. Different pathogenic variants in the TIA1 gene, distinct from the founder 1, have recently been associated with frontotemporal dementia and amyotrophic lateral sclerosis (ALS), suggesting that TIA1-related disorders belong to the group of multisystem proteinopathies. We describe the first case of a two-generation family with the founder E384K TIA1 mutation demonstrating phenotypic variability; the mother manifested as Welander myopathy, whereas 2 daughters manifested as ALS. No other genetic cause of ALS was found in 1 of the affected daughters. We also discuss the possible mechanisms explaining this pleotropic presentation of the founder mutation.
    DOI:  https://doi.org/10.1097/CND.0000000000000501
  6. Expert Opin Ther Targets. 2024 Aug 22. 1-12
    VPS35 or retromer as a potential target for neurodegenerative disorders: barriers to progress.
    Anika Wu, Daehoon Lee, Wen-Cheng Xiong.
       INTRODUCTION: Vacuolar Protein Sorting 35 (VPS35) is pivotal in the retromer complex, governing transmembrane protein trafficking within cells, and its dysfunction is implicated in neurodegenerative diseases. A missense mutation, Asp620Asn (D620N), specifically ties to familial late-onset Parkinson's, while reduced VPS35 levels are observed in Alzheimer's, amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and tauopathies. VPS35's absence in certain neurons during development can initiate neurodegeneration, highlighting its necessity for neural health. Present therapeutic research mainly targets the clearance of harmful protein aggregates and symptom management. Innovative treatments focusing on VPS35 are under investigation, although fully understanding the mechanisms and optimal targeting strategies remain a challenge.
    AREAS COVERED: This review offers a detailed account of VPS35's discovery, its role in neurodegenerative mechanisms - especially in Parkinson's and Alzheimer's - and its link to other disorders. It shines alight on recent insights into VPS35's function in development, disease, and as a therapeutic target.
    EXPERT OPINION: VPS35 is integral to cellular function and disease association, making it a significant candidate for developing therapies. Progress in modulating VPS35's activity may lead to breakthrough treatments that not only slow disease progression but may also act as biomarkers for neurodegeneration risk, marking a step forward in managing these complex conditions.
    Keywords:  Alzheimer’s disease; Parkinson’s disease; VPS35; neurodegenerative diseases; retromer
    DOI:  https://doi.org/10.1080/14728222.2024.2392700
  7. Sci Adv. 2024 Aug 23. 10(34): eadn6016
    Phosphoglycerate kinase is a central leverage point in Parkinson's disease-driven neuronal metabolic deficits.
    Alexandros C Kokotos, Aldana M Antoniazzi, Santiago R Unda, Myung Soo Ko, Daehun Park, David Eliezer, Michael G Kaplitt, Pietro De Camilli, Timothy A Ryan.
      Although certain drivers of familial Parkinson's disease (PD) compromise mitochondrial integrity, whether metabolic deficits underly other idiopathic or genetic origins of PD is unclear. Here, we demonstrate that phosphoglycerate kinase 1 (PGK1), a gene in the PARK12 susceptibility locus, is rate limiting in neuronal glycolysis and that modestly increasing PGK1 expression boosts neuronal adenosine 5'-triphosphate production kinetics that is sufficient to suppress PARK20-driven synaptic dysfunction. We found that this activity enhancement depends on the molecular chaperone PARK7/DJ-1, whose loss of function significantly disrupts axonal bioenergetics. In vivo, viral expression of PGK1 confers protection of striatal dopamine axons against metabolic lesions. These data support the notion that bioenergetic deficits may underpin PD-associated pathologies and point to improving neuronal adenosine 5'-triphosphate production kinetics as a promising path forward in PD therapeutics.
    DOI:  https://doi.org/10.1126/sciadv.adn6016
  8. Front Neural Circuits. 2024 ;18 1453958
    Recent advances and applications of human brain models.
    Kaneyasu Nishimura, Hironobu Osaki, Kotaro Tezuka, Daisuke Nakashima, Shintaro Numata, Yoshito Masamizu.
      Recent advances in human pluripotent stem cell (hPSC) technologies have prompted the emergence of new research fields and applications for human neurons and brain organoids. Brain organoids have gained attention as an in vitro model system that recapitulates the higher structure, cellular diversity and function of the brain to explore brain development, disease modeling, drug screening, and regenerative medicine. This progress has been accelerated by abundant interactions of brain organoid technology with various research fields. A cross-disciplinary approach with human brain organoid technology offers a higher-ordered advance for more accurately understanding the human brain. In this review, we summarize the status of neural induction in two- and three-dimensional culture systems from hPSCs and the modeling of neurodegenerative diseases using brain organoids. We also highlight the latest bioengineered technologies for the assembly of spatially higher-ordered neural tissues and prospects of brain organoid technology toward the understanding of the potential and abilities of the human brain.
    Keywords:  assembloids; bioengineering; brain organoids; brain region-specific neurons; disease modeling; human pluripotent stem cells
    DOI:  https://doi.org/10.3389/fncir.2024.1453958
  9. Autophagy. 2024 Aug 23.
    Artificial targeting of autophagy components to mitochondria reveals both conventional and unconventional mitophagy pathways.
    Katharina C Lorentzen, Alan R Prescott, Ian G Ganley.
      Macroautophagy/autophagy enables lysosomal degradation of a diverse array of intracellular material. This process is essential for normal cellular function and its dysregulation is implicated in many diseases. Given this, there is much interest in understanding autophagic mechanisms of action in order to determine how it can be best targeted therapeutically. In mitophagy, the selective degradation of mitochondria via autophagy, mitochondria first need to be primed with signals that allow the recruitment of the core autophagy machinery to drive the local formation of an autophagosome around the target mitochondrion. To determine how the recruitment of different core autophagy components can drive mitophagy, we took advantage of the mito-QC mitophagy assay (an outer mitochondrial membrane-localized tandem mCherry-GFP tag). By tagging autophagy proteins with an anti-mCherry (or anti-GFP) nanobody, we could recruit them to mitochondria and simultaneously monitor levels of mitophagy. We found that targeting ULK1, ATG16L1 and the different Atg8-family proteins was sufficient to induce mitophagy. Mitochondrial recruitment of ULK1 and the Atg8-family proteins induced a conventional mitophagy pathway, requiring RB1CC1/FIP200, PIK3C3/VPS34 activity and ATG5. Surprisingly, the mitophagy pathway upon recruitment of ATG16L1 proceeded independently of ATG5, although it still required RB1CC1 and PIK3C3/VPS34 activity. In this latter pathway, mitochondria were alternatively delivered to lysosomes via uptake into early endosomes.
    Keywords:  ATG16L1; Atg8; ULK1; nanobody; targeted organelle degradation
    DOI:  https://doi.org/10.1080/15548627.2024.2395149
  10. Neuropathol Appl Neurobiol. 2024 Aug;50(4): e13006
    Synaptic gene expression changes in frontotemporal dementia due to the MAPT 10 + 16 mutation.
    Owen Dando, Robert McGeachan, Jamie McQueen, Paul Baxter, Nathan Rockley, Hannah McAlister, Adharsh Prasad, Xin He, Declan King, Jamie Rose, Phillip B Jones, Jane Tulloch, Siddharthan Chandran, Colin Smith, Giles Hardingham, Tara L Spires-Jones.
       AIMS: Mutations in the MAPT gene encoding tau protein can cause autosomal dominant neurodegenerative tauopathies including frontotemporal dementia (often with Parkinsonism). In Alzheimer's disease, the most common tauopathy, synapse loss is the strongest pathological correlate of cognitive decline. Recently, Positron Emission Tomography (PET) imaging with synaptic tracers revealed clinically relevant loss of synapses in primary tauopathies; however, the molecular mechanisms leading to synapse degeneration in primary tauopathies remain largely unknown. In this study, we examined post-mortem brain tissue from people who died with frontotemporal dementia with tau pathology (FTDtau) caused by the MAPT intronic exon 10 + 16 mutation, which increases splice variants containing exon 10 resulting in higher levels of tau with four microtubule-binding domains.
    METHODS: We used RNA sequencing and histopathology to examine temporal cortex and visual cortex, to look for molecular phenotypes compared to age, sex and RNA integrity matched participants who died without neurological disease (n = 12 FTDtau10 + 16 and 13 controls).
    RESULTS: Bulk tissue RNA sequencing reveals substantial downregulation of gene expression associated with synaptic function. Upregulated biological pathways in human MAPT 10 + 16 brain included those involved in transcriptional regulation, DNA damage response and neuroinflammation. Histopathology confirmed increased pathological tau accumulation in FTDtau10 + 16 cortex as well as a loss of presynaptic protein staining and region-specific increased colocalization of phospho-tau with synapses in temporal cortex.
    CONCLUSIONS: Our data indicate that synaptic pathology likely contributes to pathogenesis in FTDtau10 + 16 caused by the MAPT 10 + 16 mutation.
    Keywords:  frontotemporal dementia; synapse; tau
    DOI:  https://doi.org/10.1111/nan.13006
  11. FASEB J. 2024 Aug 31. 38(16): e70009
    Quercetin induces a slow myofiber phenotype in engineered human skeletal muscle tissues.
    Akitoshi Nagai, Yoshihisa Kaneda, Takayuki Izumo, Yoshihiro Nakao, Hiroyuki Honda, Kazunori Shimizu.
      Skeletal muscle comprises slow and fast myofibers, with slow myofibers excelling in aerobic metabolism and endurance. Quercetin, a polyphenol, is reported to induce slow myofibers in rodent skeletal muscle both in vitro and in vivo. However, its effect on human myofiber types remains unexplored. In this study, we evaluated quercetin's impact on slow myofiber induction using human skeletal muscle satellite cells. In a two-dimensional culture, quercetin enhanced gene expression, contributing to muscle differentiation, and significantly expanded the area of slow-type myosin heavy chain positive cells. It also elevated the gene expression of Pgc1α, an inducer of slow myofibers. Conversely, quercetin did not affect mitochondrial abundance, fission, or fusion, but it did increase the gene expression of Cox7A2L, which aids in promoting mitochondrial supercomplexity and endurance, and Mb, which contributes to oxidative phosphorylation. In a three-dimensional culture, quercetin significantly extended the time to peak tension and half relaxation time of the engineered human skeletal muscle tissues constructed on microdevices. Moreover, quercetin enhanced the muscle endurance of the tissues and curbed the rise in lactate secretion from the exercised tissues. These findings suggest that quercetin may induce slow myofibers in human skeletal muscle.
    DOI:  https://doi.org/10.1096/fj.202400914RR
  12. J Transl Med. 2024 Aug 22. 22(1): 783
    Toward the latest advancements in cardiac regeneration using induced pluripotent stem cells (iPSCs) technology: approaches and challenges.
    Seyedeh Parya Farboud, Ezzatollah Fathi, Behnaz Valipour, Raheleh Farahzadi.
      A novel approach to treating heart failures was developed with the introduction of iPSC technology. Knowledge in regenerative medicine, developmental biology, and the identification of illnesses at the cellular level has exploded since the discovery of iPSCs. One of the most frequent causes of mortality associated with cardiovascular disease is the loss of cardiomyocytes (CMs), followed by heart failure. A possible treatment for heart failure involves restoring cardiac function and replacing damaged tissue with healthy, regenerated CMs. Significant strides in stem cell biology during the last ten years have transformed the in vitro study of human illness and enhanced our knowledge of the molecular pathways underlying human disease, regenerative medicine, and drug development. We seek to examine iPSC advancements in disease modeling, drug discovery, iPSC-Based cell treatments, and purification methods in this article.
    Keywords:  Cardiac regeneration; Regenerative medicine; Signaling pathways; Stem cell-based therapy; iPSC
    DOI:  https://doi.org/10.1186/s12967-024-05499-8
  13. CNS Neurol Disord Drug Targets. 2024 Aug 21.
    Amyotrophic Lateral Sclerosis (ALS): An Overview of Genetic and Metabolic Signaling Mechanisms.
    José Augusto Nogueira-Machado, Francisco das Chagas Lima E Silva, Fabiana Rocha E Silva, Nathalia Gomes.
      Amyotrophic Lateral Sclerosis (ALS) is a rare, progressive, and incurable disease. Sporadic (sALS) accounts for ninety percent of ALS cases, while familial ALS (fALS) accounts for around fifteen percent. Reports have identified over 30 different forms of familial ALS. Multiple types of fALS exhibit comparable symptoms with mutations in different genes and possibly with different predominant metabolic signals. Clinical diagnosis takes into account patient history but not genetic mutations, misfolded proteins, or metabolic signaling. As research on genetics and metabolic pathways advances, it is expected that the intricate complexity of ALS will compound further. Clinicians discuss whether a gene's presence is a cause of the disease or just an association or consequence. They believe that a mutant gene alone is insufficient to diagnose ALS. ALS, often perceived as a single disease, appears to be a complex collection of diseases with similar symptoms. This review highlights gene mutations, metabolic pathways, and muscle-neuron interactions.
    Keywords:  ALS; Amyotrophic lateral sclerosis; genetic biomarkers; metabolic signaling; muscle-neuron interaction; mutated ALS genes; neurodegenerative diseases.; neurological implications
    DOI:  https://doi.org/10.2174/0118715273315891240801065231
  14. Sci Rep. 2024 08 22. 14(1): 19540
    The ALS-associated KIF5A P986L variant is not pathogenic for Drosophila motoneurons.
    Sophie Layalle, Franck Aimond, Véronique Brugioti, Claire Guissart, Cédric Raoul, Laurent Soustelle.
      Amyotrophic lateral sclerosis (ALS) is a devastating paralytic disorder caused by the death of motoneurons. Several mutations in the KIF5A gene have been identified in patients with ALS. Some mutations affect the splicing sites of exon 27 leading to its deletion (Δ27 mutation). KIF5A Δ27 is aggregation-prone and pathogenic for motoneurons due to a toxic gain of function. Another mutation found to be enriched in ALS patients is a proline/leucine substitution at position 986 (P986L mutation). Bioinformatic analyses strongly suggest that this variant is benign. Our study aims to conduct functional studies in Drosophila to classify the KIF5A P986L variant. When expressed in motoneurons, KIF5A P986L does not modify the morphology of larval NMJ or the synaptic transmission. In addition, KIF5A P986L is uniformly distributed in axons and does not disturb mitochondria distribution. Locomotion at larval and adult stages is not affected by KIF5A P986L. Finally, both KIF5A WT and P986L expression in adult motoneurons extend median lifespan compared to control flies. Altogether, our data show that the KIF5A P986L variant is not pathogenic for motoneurons and may represent a hypomorphic allele, although it is not causative for ALS.
    DOI:  https://doi.org/10.1038/s41598-024-70543-y
  15. Cell Mol Life Sci. 2024 Aug 20. 81(1): 362
    RXR nuclear receptor signaling modulates lipid metabolism and triggers lysosomal clearance of alpha-synuclein in neuronal models of synucleinopathy.
    Arati Tripathi, Heba Alnakhala, Lisa Brontesi, Dennis Selkoe, Ulf Dettmer.
      Disease-modifying strategies for Parkinson disease (PD), the most common synucleinopathy, represent a critical unmet medical need. Accumulation of the neuronal protein alpha-synuclein (αS) and abnormal lipid metabolism have each been implicated in PD pathogenesis. Here, we elucidate how retinoid-X-receptor (RXR) nuclear receptor signaling impacts these two aspects of PD pathogenesis. We find that activated RXR differentially regulates fatty acid desaturases, significantly reducing the transcript levels of the largely brain-specific desaturase SCD5 in human cultured neural cells and PD patient-derived neurons. This was associated with reduced perilipin-2 protein levels in patient neurons, reversal of αS-induced increases in lipid droplet (LD) size, and a reduction of triglyceride levels in human cultured cells. With regard to αS proteostasis, our study reveals that RXR agonism stimulates lysosomal clearance of αS. Our data support the involvement of Polo-like kinase 2 activity and αS S129 phosphorylation in mediating this benefit. The lowering of cellular αS levels was associated with reduced cytotoxicity. Compared to RXR activation, the RXR antagonist HX531 had the opposite effects on LD size, SCD, αS turnover, and cytotoxicity, all supporting pathway specificity. Together, our findings show that RXR-activating ligands can modulate fatty acid metabolism and αS turnover to confer benefit in cellular models of PD, including patient neurons. We offer a new paradigm to investigate nuclear receptor ligands as a promising strategy for PD and related synucleinopathies.
    Keywords:  Alpha-synuclein; Desaturases; Fatty acids; Nuclear receptor; Parkinson’s disease; Retinoid X Receptor agonist; SNCA triplication
    DOI:  https://doi.org/10.1007/s00018-024-05373-2
  16. Nat Commun. 2024 Aug 16. 15(1): 7058
    Motion blur microscopy: in vitro imaging of cell adhesion dynamics in whole blood flow.
    Utku Goreke, Ayesha Gonzales, Brandon Shipley, Madeleine Tincher, Oshin Sharma, William J Wulftange, Yuncheng Man, Ran An, Michael Hinczewski, Umut A Gurkan.
      Imaging and characterizing the dynamics of cellular adhesion in blood samples is of fundamental importance in understanding biological function. In vitro microscopy methods are widely used for this task but typically require diluting the blood with a buffer to allow for transmission of light. However, whole blood provides crucial signaling cues that influence adhesion dynamics, which means that conventional approaches lack the full physiological complexity of living microvasculature. We can reliably image cell interactions in microfluidic channels during whole blood flow by motion blur microscopy (MBM) in vitro and automate image analysis using machine learning. MBM provides a low cost, easy to implement alternative to intravital microscopy, for rapid data generation where understanding cell interactions, adhesion, and motility is crucial. MBM is generalizable to studies of various diseases, including cancer, blood disorders, thrombosis, inflammatory and autoimmune diseases, as well as providing rich datasets for theoretical modeling of adhesion dynamics.
    DOI:  https://doi.org/10.1038/s41467-024-51014-4
  17. Prog Brain Res. 2024 ;pii: S0079-6123(24)00088-8. [Epub ahead of print]289 81-105
    Coffee and amyotrophic lateral sclerosis (ALS).
    Adejoke Elizabeth Memudu, Baliqis Adejoke Olukade, Oluwatosin Samuel Adebayo, Muhammad Liaquat Raza.
      Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disorder characterized by progressive loss of motor neurons. The effective treatments for ALS remain elusive, necessitating exploration into novel preventive strategies. ALS pathogenesis is triggered by oxidative stress which results in neuroinflammation, exicitotoxicity and neuronal cell death. Nutritional mechanism for halting progression of neurodegeneration is through dietary compounds with antioxidants, anti-inflammatory or neuromodulating activity. Coffee is a widely consumed beverage made up of polyphenols, caffeine and other compounds with possible antioxidants and neuro-protective roles. It is important to say that various epidemiological studies have documented association between coffee intake and ALS. This chapter is aimed to present a comprehensive review of existing literature on coffee consumption and ALS, involving epidemiological studies, preclinical research, and its mechanism of actions in animal model of ALS. It highlights key findings regarding the potential neuroprotective properties of coffee constituents such as caffeine, polyphenols, and other bioactive compounds. Furthermore, it discusses possible pathways through which coffee may modulate ALS pathogenesis, including suppressing oxidative stress and neuroinflammation while boosting adenosine function via the adenosine receptor two on the motor neuron cells membrane in the spinal cord to enhance motor function via the corticospinal tract. Overall, this chapter underscores the significance of further research to unravel the specific mechanisms by which coffee exerts its neuroprotective effects in ALS, with the ultimate goal of identifying dietary strategies for ALS prevention and management.
    Keywords:  Amyotrophic lateral sclerosis; Caffeine; Coffee; Neuroinflammation; Neuroprotection; Oxidative stress; Polyphenols
    DOI:  https://doi.org/10.1016/bs.pbr.2024.06.003
  18. Science. 2024 Aug 23. 385(6711): eado2032
    The actin-spectrin submembrane scaffold restricts endocytosis along proximal axons.
    Florian Wernert, Satish Babu Moparthi, Florence Pelletier, Jeanne Lainé, Eline Simons, Gilles Moulay, Fanny Rueda, Nicolas Jullien, Sofia Benkhelifa-Ziyyat, Marie-Jeanne Papandréou, Christophe Leterrier, Stéphane Vassilopoulos.
      Clathrin-mediated endocytosis has characteristic features in neuronal dendrites and presynapses, but how membrane proteins are internalized along the axon shaft remains unclear. We focused on clathrin-coated structures and endocytosis along the axon initial segment (AIS) and their relationship to the periodic actin-spectrin scaffold that lines the axonal plasma membrane. A combination of super-resolution microscopy and platinum-replica electron microscopy on cultured neurons revealed that AIS clathrin-coated pits form within "clearings", circular areas devoid of actin-spectrin mesh. Actin-spectrin scaffold disorganization increased clathrin-coated pit formation. Cargo uptake and live-cell imaging showed that AIS clathrin-coated pits are particularly stable. Neuronal plasticity-inducing stimulation triggered internalization of the clathrin-coated pits through polymerization of branched actin around them. Thus, spectrin and actin regulate clathrin-coated pit formation and scission to control endocytosis at the AIS.
    DOI:  https://doi.org/10.1126/science.ado2032
  19. Commun Biol. 2024 Aug 18. 7(1): 1014
    Peripheral sequestration of huntingtin delays neuronal death and depends on N-terminal ubiquitination.
    Ayub Boulos, Dunia Maroun, Aaron Ciechanover, Noam E Ziv.
      Huntington's disease (HD) is caused by a glutamine repeat expansion in the protein huntingtin. Mutated huntingtin (mHtt) forms aggregates whose impacts on neuronal survival are still debated. Using weeks-long, continual imaging of cortical neurons, we find that mHtt is gradually sequestrated into peripheral, mainly axonal aggregates, concomitant with dramatic reductions in cytosolic mHtt levels and enhanced neuronal survival. in-situ pulse-chase imaging reveals that aggregates continually gain and lose mHtt, in line with these acting as mHtt sinks at equilibrium with cytosolic pools. Mutating two N-terminal lysines found to be ubiquitinated in HD animal models suppresses peripheral aggregate formation and reductions in cytosolic mHtt, promotes nuclear aggregate formation, stabilizes aggregates and leads to pervasive neuronal death. These findings demonstrate the capacity of aggregates formed at peripheral locations to sequester away cytosolic, presumably toxic mHtt forms and support a crucial role for N-terminal ubiquitination in promoting these processes and delaying neuronal death.
    DOI:  https://doi.org/10.1038/s42003-024-06733-1
  20. F1000Res. 2024 ;13 817
    A guide to selecting high-performing antibodies for Synaptotagmin-1 (Uniprot ID P21579) for use in western blot, immunoprecipitation, immunofluorescence and flow cytometry.
    NeuroSGC/YCharOS/EDDU collaborative group
      Synaptotagmin-1 is a synaptic vesicle transmembrane protein that senses calcium influx via its tandem C2-domains, triggering synchronous neurotransmitter release. Disruption to SYT1 is associated with neurodevelopmental disorders, highlighting the importance of identifying high-quality research reagents to enhance understanding of Synaptotagmin-1 in health and disease. Here we have characterized thirteen Synaptotagmin-1 commercial antibodies for western blot, immunoprecipitation, immunofluorescence and flow cytometry using a standardized experimental protocol based on comparing read-outs in knockout cell lines and isogenic parental controls. These studies are part of a larger, collaborative initiative seeking to address antibody reproducibility issues by characterizing commercially available antibodies for human proteins and publishing the results openly as a resource for the scientific community. While use of antibodies and protocols vary between laboratories, we encourage readers to use this report as a guide to select the most appropriate antibodies for their specific needs.
    Keywords:  SYT1; Synaptotagmin-1; Uniprot ID P21579; antibody characterization; antibody validation; immunofluorescence; immunoprecipitation; western blot
    DOI:  https://doi.org/10.12688/f1000research.154034.1
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