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Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis.

Acta neuropathologica · 2022 · 144(3): 413-435

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it …

PMID 35778567 DOI ↗

MECP2-related pathways are dysregulated in a cortical organoid model of myotonic dystrophy.

Science translational medicine · 2022 · 14(651): eabn2375

Myotonic dystrophy type 1 (DM1) is a multisystem, autosomal-dominant inherited disorder caused by CTG microsatellite repeat expansions (MREs) in the 3' untranslated region of the dystrophia myotonica-protein kinase (<i>DMPK</i>) gene. Despite its prominence as the most common adult-onset muscular dystrophy, …

PMID 35767654 DOI ↗

Persistent mRNA localization defects and cell death in ALS neurons caused by transient cellular stress.

Cell reports · 2021 · 36(10): 109685

Persistent cytoplasmic aggregates containing RNA binding proteins (RBPs) are central to the pathogenesis of late-onset neurodegenerative disorders such as amyotrophic lateral sclerosis (ALS). These aggregates share components, molecular mechanisms, and cellular protein quality control pathways with stress-induced RNA granules (SGs). …

PMID 34496257 DOI ↗

Huntington's disease mice and human brain tissue exhibit increased G3BP1 granules and TDP43 mislocalization.

The Journal of clinical investigation · 2021 · 131(12)

Chronic cellular stress associated with neurodegenerative disease can result in the persistence of stress granule (SG) structures, membraneless organelles that form in response to cellular stress. In Huntington's disease (HD), chronic expression of mutant huntingtin generates various forms of cellular …

PMID 33945510 DOI ↗

S-nitrosylated TDP-43 triggers aggregation, cell-to-cell spread, and neurotoxicity in hiPSCs and in vivo models of ALS/FTD.

Proceedings of the National Academy of Sciences of the United States of America · 2021 · 118(11)

Rare genetic mutations result in aggregation and spreading of cognate proteins in neurodegenerative disorders; however, in the absence of mutation (i.e., in the vast majority of "sporadic" cases), mechanisms for protein misfolding/aggregation remain largely unknown. Here, we show environmentally induced …

PMID 33692125 DOI ↗

G₄C₂ Repeat RNA Initiates a POM121-Mediated Reduction in Specific Nucleoporins in C9orf72 ALS/FTD.

Neuron · 2020 · 107(6): 1124-1140.e11

Through mechanisms that remain poorly defined, defects in nucleocytoplasmic transport and accumulations of specific nuclear-pore-complex-associated proteins have been reported in multiple neurodegenerative diseases, including C9orf72 Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (ALS/FTD). Using super-resolution structured illumination microscopy, we have explored …

PMID 32673563 DOI ↗

Motoneuron expression profiling identifies an association between an axonal splice variant of HDGF-related protein 3 and peripheral myelination.

The Journal of biological chemistry · 2020 · 295(34): 12233-12246

Disorders that disrupt myelin formation during development or in adulthood, such as multiple sclerosis and peripheral neuropathies, lead to severe pathologies, illustrating myelin's crucial role in normal neural functioning. However, although our understanding of glial biology is increasing, the signals …

PMID 32647008 DOI ↗

The mRNA Decay Factor CAR-1/LSM14 Regulates Axon Regeneration via Mitochondrial Calcium Dynamics.

Current biology : CB · 2020 · 30(5): 865-876.e7

mRNA decay factors regulate mRNA turnover by recruiting non-translating mRNAs and targeting them for translational repression and mRNA degradation. How mRNA decay pathways regulate cellular function in vivo with specificity is poorly understood. Here, we show that C. elegans mRNA …

PMID 31983639 DOI ↗

Corrigendum: Patch-Seq Protocol to Analyze the Electrophysiology, Morphology and Transcriptome of Whole Single Neurons Derived From Human Pluripotent Stem Cells.

Frontiers in molecular neuroscience · 2019 · 12: 150

[This corrects the article DOI: 10.3389/fnmol.2018.00261.].

PMID 31244603 DOI ↗

Small-Molecule Modulation of TDP-43 Recruitment to Stress Granules Prevents Persistent TDP-43 Accumulation in ALS/FTD.

Neuron · 2019 · 103(5): 802-819.e11

Stress granules (SGs) form during cellular stress and are implicated in neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal dementia (ALS/FTD). To yield insights into the role of SGs in pathophysiology, we performed a high-content screen to identify small …

PMID 31272829 DOI ↗

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease.

Cell stem cell · 2019 · 24(6): 1006

PMID 31173705 DOI ↗

Disruption of RNA Metabolism in Neurological Diseases and Emerging Therapeutic Interventions.

Neuron · 2019 · 102(2): 294-320

RNA binding proteins are critical to the maintenance of the transcriptome via controlled regulation of RNA processing and transport. Alterations of these proteins impact multiple steps of the RNA life cycle resulting in various molecular phenotypes such as aberrant RNA …

PMID 30998900 DOI ↗

Glial cells maintain synapses by inhibiting an activity-dependent retrograde protease signal.

PLoS genetics · 2019 · 15(3): e1007948

Glial cells regulate multiple aspects of synaptogenesis. In the absence of Schwann cells, a peripheral glial cell, motor neurons initially innervate muscle but then degenerate. Here, using a genetic approach, we show that neural activity-regulated negative factors produced by muscle …

PMID 30870413 DOI ↗

Patch-Seq Protocol to Analyze the Electrophysiology, Morphology and Transcriptome of Whole Single Neurons Derived From Human Pluripotent Stem Cells.

Frontiers in molecular neuroscience · 2018 · 11: 261

The human brain is composed of a complex assembly of about 171 billion heterogeneous cellular units (86 billion neurons and 85 billion non-neuronal glia cells). A comprehensive description of brain cells is necessary to understand the nervous system in health …

PMID 30147644 DOI ↗

Transcriptome-pathology correlation identifies interplay between TDP-43 and the expression of its kinase CK1E in sporadic ALS.

Acta neuropathologica · 2018 · 136(3): 405-423

Sporadic amyotrophic lateral sclerosis (sALS) is the most common form of ALS, however, the molecular mechanisms underlying cellular damage and motor neuron degeneration remain elusive. To identify molecular signatures of sALS we performed genome-wide expression profiling in laser capture microdissection-enriched …

PMID 29881994 DOI ↗

Tissue-selective restriction of RNA editing of CaV1.3 by splicing factor SRSF9.

Nucleic acids research · 2018 · 46(14): 7323-7338

Adenosine DeAminases acting on RNA (ADAR) catalyzes adenosine-to-inosine (A-to-I) conversion within RNA duplex structures. While A-to-I editing is often dynamically regulated in a spatial-temporal manner, the mechanisms underlying its tissue-selective restriction remain elusive. We have previously reported that transcripts of …

PMID 29733375 DOI ↗

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease.

Cell stem cell · 2018 · 23(1): 123-131.e6

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of midbrain neurons (MBNs). Recent evidence suggests contribution of the adaptive immune system in PD. Here, we show a role for human T lymphocytes as cell death inducers …

PMID 29979986 DOI ↗

Context-Dependent and Disease-Specific Diversity in Protein Interactions within Stress Granules.

Cell · 2018 · 172(3): 590-604.e13

Stress granules (SGs) are transient ribonucleoprotein (RNP) aggregates that form during cellular stress and are increasingly implicated in human neurodegeneration. To study the proteome and compositional diversity of SGs in different cell types and in the context of neurodegeneration-linked mutations, …

PMID 29373831 DOI ↗

Genetic mutations in RNA-binding proteins and their roles in ALS.

Human genetics · 2017 · 136(9): 1193-1214

Mutations in genes that encode RNA-binding proteins (RBPs) have emerged as critical determinants of neurological diseases, especially motor neuron disorders such as amyotrophic lateral sclerosis (ALS). RBPs are involved in all aspects of RNA processing, controlling the life cycle of …

PMID 28762175 DOI ↗

The <i>C. elegans</i> neural editome reveals an ADAR target mRNA required for proper chemotaxis.

eLife · 2017 · 6

ADAR proteins alter gene expression both by catalyzing adenosine (A) to inosine (I) RNA editing and binding to regulatory elements in target RNAs. Loss of ADARs affects neuronal function in all animals studied to date. <i>Caenorhabditis elegans</i> lacking ADARs exhibit …

PMID 28925356 DOI ↗

Single-Cell Alternative Splicing Analysis with Expedition Reveals Splicing Dynamics during Neuron Differentiation.

Molecular cell · 2017 · 67(1): 148-161.e5

Alternative splicing (AS) generates isoform diversity for cellular identity and homeostasis in multicellular life. Although AS variation has been observed among single cells, little is known about the biological or evolutionary significance of such variation. We developed Expedition, a computational …

PMID 28673540 DOI ↗

High-Throughput and Cost-Effective Characterization of Induced Pluripotent Stem Cells.

Stem cell reports · 2017 · 8(4): 1101-1111

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) offers the possibility of studying the molecular mechanisms underlying human diseases in cell types difficult to extract from living patients, such as neurons and cardiomyocytes. To date, studies have been published …

PMID 28410643 DOI ↗

MicroRNA-101 Regulates Multiple Developmental Programs to Constrain Excitation in Adult Neural Networks.

Neuron · 2016 · 92(6): 1337-1351

A critical feature of neural networks is that they balance excitation and inhibition to prevent pathological dysfunction. How this is achieved is largely unknown, although deficits in the balance contribute to many neurological disorders. We show here that a microRNA …

PMID 27939580 DOI ↗

Predicting the functional states of human iPSC-derived neurons with single-cell RNA-seq and electrophysiology.

Molecular psychiatry · 2016 · 21(11): 1573-1588

Human neural progenitors derived from pluripotent stem cells develop into electrophysiologically active neurons at heterogeneous rates, which can confound disease-relevant discoveries in neurology and psychiatry. By combining patch clamping, morphological and transcriptome analysis on single-human neurons in vitro, we defined …

PMID 27698428 DOI ↗

Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System.

Neuron · 2016 · 92(4): 780-795

HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide crosslinking and immunoprecipitation in mouse spinal cord discover UAGG motifs enriched within ∼2,500 hnRNP A2/B1 binding sites and an unexpected role …

PMID 27773581 DOI ↗