A5001542140- Amyotrophic Lateral Sclerosis Research
- RNA Research and Splicing
- Neurogenetic and Muscular Disorders Research
- Parkinson's Disease Mechanisms and Treatments
- Ubiquitin and proteasome pathways
- Genetic Neurodegenerative Diseases
- Hereditary Neurological Disorders
- Axon Guidance and Neuronal Signaling
- biodegradable polymer synthesis and properties
- Metabolism and Genetic Disorders
- Nuclear Structure and Function
- Wnt/β-catenin signaling in development and cancer
- Hippo pathway signaling and YAP/TAZ
- Endoplasmic Reticulum Stress and Disease
- Histone Deacetylase Inhibitors Research
- Autophagy in Disease and Therapy
- Folate and B Vitamins Research
- Prion Diseases and Protein Misfolding
- Neurological diseases and metabolism
- Mitochondrial Function and Pathology
- Asthma and respiratory diseases
- Blood properties and coagulation
- Cholinesterase and Neurodegenerative Diseases
- Bone and Joint Diseases
- Protein Tyrosine Phosphatases
Massachusetts General Hospital
2024
Harvard University
2024
Children's Hospital of Pittsburgh
2016-2023
University of Pittsburgh Medical Center
2016-2023
University of Pittsburgh
2016-2021
Abstract Nuclear clearance and cytoplasmic accumulations of the RNA-binding protein TDP-43 are pathological hallmarks in almost all patients with amyotrophic lateral sclerosis (ALS) up to 50% frontotemporal dementia (FTD) Alzheimer’s disease. In disease, pathology is predominantly observed limbic system correlates cognitive decline reduced hippocampal volume. Disruption nuclear function leads abnormal RNA splicing incorporation erroneous cryptic exons numerous transcripts including...
Abstract A G4C2 hexanucleotide repeat expansion in the C9orf72 gene is most common genetic cause of ALS and FTLD (C9-ALS/FTLD) with cytoplasmic TDP-43 inclusions observed regions neurodegeneration. The accumulation repetitive RNAs dipeptide protein (DPR) are two proposed mechanisms toxicity C9-ALS/FTLD linked to impaired nucleocytoplasmic transport. Nucleocytoplasmic transport regulated by phenylalanine-glycine nucleoporins (FG nups) that comprise nuclear pore complex (NPC) permeability...
Aggregation of TAR-DNA-binding protein 43 (TDP-43) and its fragments TDP-25 TDP-35 occurs in amyotrophic lateral sclerosis (ALS). act as seeds for TDP-43 aggregation, altering function exerting toxicity. Thus, inhibition aggregation promotion their degradation may protect against cellular damage. Upregulation HSPB8 is one possible approach this purpose, since chaperone promotes the clearance an ALS associated upregulated surviving motor neurones transgenic mice human patients. We report that...
Traumatic brain injury (TBI) is a predisposing factor for many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), Parkinson's (PD), and chronic traumatic encephalopathy (CTE). Although defects in nucleocytoplasmic transport (NCT) reported ALS other whether NCT occur TBI remains unknown. We performed proteomic analysis on
Abstract Background Amyotrophic lateral sclerosis (ALS) is an adult-onset, fatal neurodegenerative disease characterized by progressive loss of upper and lower motor neurons. While pathogenic mutations in the DNA/RNA-binding protein Matrin-3 (MATR3) are linked to ALS distal myopathy, molecular mechanisms underlying MATR3-mediated neuromuscular degeneration remain unclear. Methods We generated Drosophila lines with transgenic insertion human MATR3 wildtype, disease-associated variants F115C...
Spinocerebellar ataxia type 35 (SCA35) is a rare autosomal-dominant neurodegenerative disease caused by mutations in the TGM6 gene, which codes for transglutaminase 6 (TG6). Mutations TG6 induce cerebellar degeneration an unknown mechanism. We identified seven patients bearing new TGM6. To gain insights into molecular basis of mutant TG6-induced neurotoxicity, we analyzed all mutants and five previously linked to SCA35. found that wild-type (TG6-WT) protein mainly localized nucleus...
Amyotrophic Lateral Sclerosis (ALS), a late-onset neurodegenerative disorder characterized by the loss of motor neurons in central nervous system, has no known cure to-date. Disease causing mutations human Fused Sarcoma (FUS) leads to aggressive and juvenile onset ALS. FUS is well-conserved protein across different species, which plays crucial role regulating aspects RNA metabolism. Targeted misexpression Drosophila model recapitulates several interesting phenotypes relevant ALS including...
Members of the conserved ubiquilin (UBQLN) family ubiquitin (Ub) chaperones harbor an antipodal UBL (Ub-like)-UBA (Ub-associated) domain arrangement and participate in proteasome autophagosome-mediated protein degradation. Mutations a proline-rich-repeat region (PRR) UBQLN2 cause amyotrophic lateral sclerosis (ALS)/frontotemporal dementia (FTD); however, neither normal functions PRR nor impacts ALS-associated mutations within it are well understood. In this study, we show that ALS perturb...
Abstract Mutations in fused sarcoma (FUS) lead to amyotrophic lateral sclerosis (ALS) with varying ages of onset, progression and severity. This suggests that unknown genetic factors contribute disease pathogenesis. Here we show the identification muscleblind as a novel modifier FUS-mediated neurodegeneration vivo. Muscleblind regulates cytoplasmic mislocalization mutant FUS subsequent accumulation stress granules, dendritic morphology toxicity mammalian neuronal human iPSC-derived neurons....
Abstract The most common genetic cause of amyotrophic lateral sclerosis (ALS) is a GGGGCC (G4C2) hexanucleotide repeat expansions in first intron the C9orf72 gene. accumulation repetitive RNA sequences can mediate toxicity potentially through formation intranuclear foci that sequester key RNA-binding proteins (RBPs), and non-ATG mediated translation into toxic dipeptide protein repeats. However, contribution RBP sequestration to mechanisms underlying RNA-mediated remain unknown. Here we show...
Mutations in the ubiquitin (Ub) chaperone Ubiquilin 2 (UBQLN2 ) cause X-linked forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) through unknown mechanisms. Here, we show that aggregation-prone, ALS-associated mutants UBQLN2 ALS trigger heat stress-dependent neurodegeneration Drosophila . A genetic modifier screen implicated endolysosomal axon guidance genes, including netrin receptor, Unc-5, as key modulators toxicity. Reduced gene dosage Unc-5 or its coreceptor...
TDP-43 is a predominantly nuclear DNA/RNA binding protein that often mislocalized into insoluble cytoplasmic inclusions in post-mortem patient tissue variety of neurodegenerative disorders including Amyotrophic Lateral Sclerosis (ALS) and Frontotemporal dementia (FTD). The underlying causes proteinopathies remain unclear, but recent studies indicate the formation these assemblies driven by aberrant phase transitions RNA deficient TDP-43. Technical limitations have prevented our ability to...
Abstract Amyotrophic lateral sclerosis (ALS) and Frontotemporal Lobar Degeneration (FTLD) share clinical, neuropathological, genetic features. This includes common disease-causing mutations such as the expanded G4C2 repeat in C9orf72 gene (C9-ALS/FTLD) cytoplasmic insoluble protein depositions of TDP-43 degenerating regions brain spinal cord. Proposed mechanisms toxicity C9-ALS/FTLD are production expansion transcripts their dipeptide proteins (DPRs) products which hypothesized to drive...