A5059675899- Ion Channels and Receptors
- Hereditary Neurological Disorders
- Ion channel regulation and function
- Neurological diseases and metabolism
- Genetic Neurodegenerative Diseases
- Endoplasmic Reticulum Stress and Disease
- Hearing, Cochlea, Tinnitus, Genetics
- Autophagy in Disease and Therapy
- Plant Stress Responses and Tolerance
- Neurogenetic and Muscular Disorders Research
- Peripheral Neuropathies and Disorders
- Cellular transport and secretion
- Ubiquitin and proteasome pathways
- Connexins and lens biology
- Infectious Encephalopathies and Encephalitis
- RNA regulation and disease
- Connective tissue disorders research
- Infectious Diseases and Tuberculosis
- Hedgehog Signaling Pathway Studies
- Histone Deacetylase Inhibitors Research
- Lysosomal Storage Disorders Research
- Erythrocyte Function and Pathophysiology
- Vasculitis and related conditions
- Myasthenia Gravis and Thymoma
- Amyotrophic Lateral Sclerosis Research
National Hospital for Neurology and Neurosurgery
2023-2024
University College London
2023-2024
Johns Hopkins Medicine
1993-2024
Johns Hopkins University
1993-2024
University of Michigan
2024
Massachusetts General Hospital
2014-2024
University of Iowa Health Care
2024
University of Colorado Anschutz Medical Campus
2024
Research Network (United States)
2023
Mayo Clinic
2018
Abstract Crosstalk between ion channels and small GTPases is critical during homeostasis disease, but little known about the structural underpinnings of these interactions. TRPV4 a polymodal, calcium-permeable cation channel that has emerged as potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease. Here, we present cryo-EM structures human complex with RhoA ligand-free, antagonist-bound closed, agonist-bound open states....
Abstract Intrinsically disordered regions (IDRs) are essential for membrane receptor regulation but often remain unresolved in structural studies. TRPV4, a member of the TRP vanilloid channel family involved thermo- and osmosensation, has large N-terminal IDR approximately 150 amino acids. With an integrated biology approach, we analyze ensemble TRPV4 network antagonistic regulatory elements it encodes. These modulate activity hierarchical lipid-dependent manner through transient long-range...
Blood-CNS barrier disruption is a hallmark of numerous neurological disorders, yet whether breakdown sufficient to trigger neurodegenerative disease remains unresolved. Therapeutic strategies mitigate hyperpermeability are also limited. Dominant missense mutations the cation channel transient receptor potential vanilloid 4 (TRPV4) cause forms hereditary motor neuron disease. To gain insights into cellular basis these we generated knock-in mouse models TRPV4 channelopathy by introducing two...
Rab GTPases are molecular switches that orchestrate vesicular trafficking, maturation and fusion by cycling between an active, GTP-bound form, inactive, GDP-bound form. The activity cycle is coupled to GTP hydrolysis tightly controlled regulatory proteins. Missense mutations of the GTPase Rab7 cause a dominantly inherited axonal degeneration known as Charcot-Marie-Tooth type 2B through unknown mechanism. We present 2.8 Å crystal structure L129F mutant which reveals normal conformations...
Abstract Mitofusin-2 (MFN2) is one of two ubiquitously expressed homologous proteins in eukaryote cells, playing a critical role mitochondrial fusion. Mutations MFN2 (most commonly autosomal dominant) cause Charcot-Marie-Tooth disease type 2A (CMT2A), the commonest axonal form CMT, with significant allelic heterogeneity. Previous, moderately-sized, cross sectional genotype-phenotype studies CMT2A have described phenotypic spectrum disease, but longitudinal natural history are lacking. In...
Abstract The cation channel transient receptor potential vanilloid 4 (TRPV4) is one of the few identified ion channels that can directly cause inherited neurodegeneration syndromes, but molecular mechanisms are unknown. Here, we show in vivo expression a neuropathy-causing TRPV4 mutant (TRPV4 R269C ) causes dose-dependent neuronal dysfunction and axonal degeneration, which rescued by genetic or pharmacological blockade activity. triggers increased intracellular Ca 2+ through...
Abstract Charcot-Marie-Tooth disease (CMT) due to GJB1 variants (CMTX1) is the second most common form of CMT. It an X-linked disorder characterized by progressive sensory and motor neuropathy with males affected more severely than females. Many reported remain classified as uncertain significance (VUS). In this large, international, multicentre study we prospectively collected demographic, clinical genetic data on patients CMT associated variants. Pathogenicity for each variant was defined...
Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease characterized by selective loss of motor neurons, muscle atrophy and paralysis. Mutations in the human VAMP-associated protein B (hVAPB) cause heterogeneous group neuron diseases including ALS8. Despite extensive research, molecular mechanisms underlying ALS pathogenesis remain largely unknown. Genetic screens for key interactors hVAPB activity intact nervous system, however, represent fundamental approach towards...
Abstract TRPV4 is a cell surface-expressed calcium-permeable cation channel that mediates cell-specific effects on cellular morphology and function. Dominant missense mutations of cause distinct, tissue-specific diseases, but the pathogenic mechanisms are unknown. Mutations causing peripheral neuropathy localize to intracellular N-terminal domain whereas skeletal dysplasia in multiple domains. Using an unbiased screen, we identified cytoskeletal remodeling GTPase RhoA as interactor....
Conditions causing an increase in misfolded or aberrant proteins can impair the activity of ubiquitin/proteasome system (UPS). This observation is particular interest, given fact that proteotoxic stress closely associated with a large variety disorders. Although impairment UPS appears to be general consequence insults, underlying mechanisms remain enigmatic. Here, we show heat shock-induced resulted conjugation ubiquitin detergent-insoluble protein aggregates, which coincided reduced levels...
Distinct dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically cause nonoverlapping diseases of either neuromuscular or skeletal systems. However, accumulating evidence suggests that some patients develop mixed phenotypes include elements both and disease. We sought to define genetic clinical features these patients.We report a 2-year-old with novel R616G mutation severe neuropathy phenotype bilateral vocal cord paralysis....
Abstract Transient receptor potential vanilloid 4 (TRPV4), a member of the TRP superfamily, is broadly expressed, cell surface‐localized cation channel that activated by variety environmental stimuli. Importantly, TRPV4 has been increasingly implicated in regulation cellular morphology. Here we propose and cytoskeletal remodeling small GTPase RhoA together constitute an environmentally sensitive signaling complex contributes to pathological alterations during neurological injury disease....
Abstract Recessive SH3TC2 variants cause Charcot-Marie-Tooth disease type 4C (CMT4C). CMT4C is typically a sensorimotor demyelinating polyneuropathy, marked by early onset spinal deformities, but its clinical characteristics and severity are quite variable. Clear relationships between pathogenic the spectrum of manifestations to date lacking. Gene replacement therapy has been shown ameliorate phenotype in mouse model CMT4C, emphasizing need for natural history studies inform trial readiness....
Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by autosomal recessive variants in the
Dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) cause diverse and largely distinct channelopathies, including inherited forms of neuromuscular disease, skeletal dysplasias arthropathy. Pathogenic gain function toxicity that can be rescued by small molecule antagonists cellular animal models, suggesting antagonism could therapeutic for patients. Numerous variants have been detected with targeted whole exome/genome sequencing, but vast...
Ubiquitin (Ub)-mediated regulation of plasmalemmal ion channel activity canonically occurs via stimulation endocytosis. Whether ubiquitination can modulate by alternative mechanisms remains unknown. Here, we show that the transient receptor potential vanilloid 4 (TRPV4) cation is multiubiquitinated within its cytosolic N-terminal and C-terminal intrinsically disordered regions (IDRs). Mutagenizing select lysine residues to block but not IDR resulted in a marked elevation TRPV4-mediated...
Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular share features motor greater than sensory dysfunction frequent vocal fold weakness. Pathogenic variants lead gain ion function that can be rescued by antagonists in cellular animal models. As small molecule have proven safe trials for other...
ATP is present in negligible concentrations the interstitium of healthy tissues but accumulates to significantly higher an inflammatory microenvironment. binds 2 categories purine receptors on surface cells, ionotropic P2X and metabotropic P2Y receptors. Included family P2X7 (P2X7R), a non-specific cation channel with unique functional structural properties that suggest it has distinct roles pathological conditions marked by increased extracellular ATP. The role P2X7R previously been...
Abstract Intrinsically disordered regions (IDRs) are essential for membrane receptor regulation but often remain unresolved in structural studies. TRPV4, a member of the TRP vanilloid channel family involved thermo- and osmosensation, has large N-terminal IDR approximately 150 amino acids. With an integrated biology approach, we analyze ensemble TRPV4 identify network regulatory elements that modulate activity hierarchical lipid-dependent manner through transient long-range interactions. A...