Clinical Outcome Assessments and Biomarkers in Charcot-Marie-Tooth Disease.

Charcot-Marie-Tooth disease (CMT) encompasses a diverse group of genetic forms of inherited peripheral neuropathy and stands as the most common hereditary neurologic disease worldwide. At present, no disease-modifying treatments exist for any form of CMT. However, promising therapeutic strategies are rapidly emerging, necessitating careful consideration of clinical outcome assessments (COAs) and clinical trial design.

Exploring P2X7 receptor antagonism as a therapeutic target for neuroprotection in an hiPSC motor neuron model.

ATP is present in negligible concentrations in the interstitium of healthy tissues but accumulates to significantly higher concentrations in an inflammatory microenvironment. ATP binds to 2 categories of purine receptors on the surface of cells, the ionotropic P2X receptors and metabotropic P2Y receptors. Included in the family of ionotropic purine receptors is P2X7 (P2X7R), a non-specific cation channel with unique functional and structural properties that suggest it has distinct roles in pathological conditions marked by increased extracellular ATP.

Clinical Characteristics of Charcot-Marie-Tooth Disease Type 4J.

Background And Objectives: Charcot-Marie-Tooth disease type 4J (CMT4J) is caused by autosomal recessive variants in the () gene. Recent preclinical work has demonstrated the feasibility of adeno-associated virus serotype 9-FIG4 gene therapy. This study aimed to further characterize the CMT4J phenotype and evaluate feasibility of validated CMT-related outcome measures for future clinical trials.

Combined clinical, structural, and cellular studies discriminate pathogenic and benign TRPV4 variants.

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, and arthropathy. Pathogenic TRPV4 mutations cause gain of ion channel function and toxicity that can be rescued by small molecule TRPV4 antagonists in cellular and animal models, suggesting that TRPV4 antagonism could be therapeutic for patients. Numerous variants in TRPV4 have been detected with targeted and whole exome/genome sequencing, but for the vast majority, their pathogenicity remains unclear.

TRPV4 neuromuscular disease registry highlights bulbar, skeletal and proximal limb manifestations.

Dominant missense mutations of the calcium-permeable cation channel TRPV4 cause Charcot-Marie-Tooth disease (CMT) type 2C and two forms of distal spinal muscular atrophy. These conditions are collectively referred to as TRPV4-related neuromuscular disease and share features of motor greater than sensory dysfunction and frequent vocal fold weakness. Pathogenic variants lead to gain of ion channel function that can be rescued by TRPV4 antagonists in cellular and animal models.

Gain-of-function mutations of TRPV4 acting in endothelial cells drive blood-CNS barrier breakdown and motor neuron degeneration in mice.

Blood-CNS barrier disruption is a hallmark of numerous neurological disorders, yet whether barrier breakdown is sufficient to trigger neurodegenerative disease remains unresolved. Therapeutic strategies to mitigate barrier hyperpermeability are also limited. Dominant missense mutations of the cation channel transient receptor potential vanilloid 4 (TRPV4) cause forms of hereditary motor neuron disease.

Crosstalk between regulatory elements in disordered TRPV4 N-terminus modulates lipid-dependent channel activity.

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 in thermo- and osmosensation, has a large N-terminal IDR of approximately 150 amino acids. With an integrated structural biology approach, we analyze the structural ensemble of the TRPV4 IDR and the network of antagonistic regulatory elements it encodes.

TRPV4-Rho GTPase complex structures reveal mechanisms of gating and disease.

Crosstalk between ion channels and small GTPases is critical during homeostasis and disease, but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions. Gain-of-function mutations also cause hereditary neuromuscular disease.

Structural insights into TRPV4-Rho GTPase signaling complex function and disease.

Crosstalk between ion channels and small GTPases is critical during homeostasis and disease , but little is known about the structural underpinnings of these interactions. TRPV4 is a polymodal, calcium-permeable cation channel that has emerged as a potential therapeutic target in multiple conditions . Gain-of-function mutations also cause hereditary neuromuscular disease .

Neuropathy due to bi-allelic SH3TC2 variants: genotype-phenotype correlation and natural history.

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 variants and the spectrum of disease manifestations are to date lacking.

Multiubiquitination of TRPV4 reduces channel activity independent of surface localization.

Ubiquitin (Ub)-mediated regulation of plasmalemmal ion channel activity canonically occurs via stimulation of endocytosis. Whether ubiquitination can modulate channel activity by alternative mechanisms remains unknown. Here, we show that the transient receptor potential vanilloid 4 (TRPV4) cation channel is multiubiquitinated within its cytosolic N-terminal and C-terminal intrinsically disordered regions (IDRs).

TRPV4: A trigger of pathological RhoA activation in neurological disease.

Transient receptor potential vanilloid 4 (TRPV4), a member of the TRP superfamily, is a broadly expressed, cell surface-localized cation channel that is activated by a variety of environmental stimuli. Importantly, TRPV4 has been increasingly implicated in the regulation of cellular morphology. Here we propose that TRPV4 and the cytoskeletal remodeling small GTPase RhoA together constitute an environmentally sensitive signaling complex that contributes to pathological cell cytoskeletal alterations during neurological injury and disease.

TRPV4 mutations causing mixed neuropathy and skeletal phenotypes result in severe gain of function.

Objective: Distinct dominant mutations in the calcium-permeable ion channel TRPV4 (transient receptor potential vanilloid 4) typically cause nonoverlapping diseases of either the neuromuscular or skeletal systems. However, accumulating evidence suggests that some patients develop mixed phenotypes that include elements of both neuromuscular and skeletal disease. We sought to define the genetic and clinical features of these patients.

Axonal Charcot-Marie-Tooth Disease: from Common Pathogenic Mechanisms to Emerging Treatment Opportunities.

Inherited peripheral neuropathies are a genetically and phenotypically diverse group of disorders that lead to degeneration of peripheral neurons with resulting sensory and motor dysfunction. Genetic neuropathies that primarily cause axonal degeneration, as opposed to demyelination, are most often classified as Charcot-Marie-Tooth disease type 2 (CMT2) and are the focus of this review. Gene identification efforts over the past three decades have dramatically expanded the genetic landscape of CMT and revealed several common pathological mechanisms among various forms of the disease.

Neuropathy-causing TRPV4 mutations disrupt TRPV4-RhoA interactions and impair neurite extension.

TRPV4 is a cell surface-expressed calcium-permeable cation channel that mediates cell-specific effects on cellular morphology and function. Dominant missense mutations of TRPV4 cause distinct, tissue-specific diseases, but the pathogenic mechanisms are unknown. Mutations causing peripheral neuropathy localize to the intracellular N-terminal domain whereas skeletal dysplasia mutations are in multiple domains.

TRPV4 disrupts mitochondrial transport and causes axonal degeneration via a CaMKII-dependent elevation of intracellular Ca.

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 the molecular mechanisms are unknown. Here, we show that in vivo expression of a neuropathy-causing TRPV4 mutant (TRPV4) causes dose-dependent neuronal dysfunction and axonal degeneration, which are rescued by genetic or pharmacological blockade of TRPV4 channel activity. TRPV4 triggers increased intracellular Ca through a Ca/calmodulin-dependent protein kinase II (CaMKII)-mediated mechanism, and CaMKII inhibition prevents both increased intracellular Ca and neurotoxicity in Drosophila and cultured primary mouse neurons.

Network analyses reveal novel aspects of ALS pathogenesis.

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 a heterogeneous group of motor neuron diseases including ALS8. Despite extensive research, the molecular mechanisms underlying ALS pathogenesis remain largely unknown.

Isolated cerebral mucormycosis of the basal ganglia.

Isolated cerebral mucormycosis is a rare fungal infection for which morbidity and mortality remain high despite prompt tissue diagnosis and antifungal treatment. Intravenous drug use is strongly associated with this condition. However, other risk factors classically associated with systemic mucormycosis, such as poorly controlled diabetes and an immunocompromised state, are seldom seen in cases of isolated cerebral involvement.

Disease mutations in Rab7 result in unregulated nucleotide exchange and inappropriate activation.

Rab GTPases are molecular switches that orchestrate vesicular trafficking, maturation and fusion by cycling between an active, GTP-bound form, and an inactive, GDP-bound form. The activity cycle is coupled to GTP hydrolysis and is tightly controlled by regulatory proteins. Missense mutations of the GTPase Rab7 cause a dominantly inherited axonal degeneration known as Charcot-Marie-Tooth type 2B through an unknown mechanism.

Selective accumulation of aggregation-prone proteasome substrates in response to proteotoxic stress.

Conditions causing an increase in misfolded or aberrant proteins can impair the activity of the ubiquitin/proteasome system (UPS). This observation is of particular interest, given the fact that proteotoxic stress is closely associated with a large variety of disorders. Although impairment of the UPS appears to be a general consequence of proteotoxic insults, the underlying mechanisms remain enigmatic.