2026-08-17 | Neuronal Prps is required for synaptic development and motor function in Drosophila melanogaster.
Phosphoribosyl pyrophosphate synthetase (PRPS) produces phosphoribosyl pyrophosphate, which is a key precursor for nucleotide biosynthesis. Mutations in the human PRPS1 gene cause Charcot-Marie-Tooth disease and other neuropathies. However, how PRPS1 dysfunction impairs neuronal and synaptic function remains unclear. In this study, we used Drosophila melanogaster to determine the effects of reduced Prps expression on neurons in vivo. Neuronal knockdown of Prps caused severe locomotor impairment in third instar larvae and in adults, which indicated a critical requirement for Prps in motor output. At the neuromuscular junction, Prpsdepletion led to a reduced number of synaptic boutons accompanied by enlargement of boutons, disrupted presynaptic active zone organization indicated by decreased Bruchpilot puncta, and loss of Futsch-positive microtubule loops. These findings suggested destabilization of cytoskeletal architecture. These phenotypes were consistently observed using independent RNAi lines. Importantly, neuronal expression of Drosophila Prps or human PRPS1 significantly rescued locomotor activity, synaptic growth, active zone organization, and microtubule structure, which are caused by the expression of the Prps short hairpin RNA. The rescue by Drosophila Prps and human PRPS1 highlights evolutionary conservation of PRPS1 function and suggests Drosophila as a model for analyzing PRPS1-associated neuropathies.
Open article ↗
2026-07-29 | A Phase 1 clinical trial to evaluate the safety and tolerability of CLZ-2002 for the treatment of patients with Charcot-Marie-Tooth disease type 1.
Charcot-Marie-Tooth disease type 1 (CMT1) is a rare, genetically diverse condition and represents the most prevalent form of inherited peripheral neuropathy, characterized by Schwann cell dysfunction resulting in progressive demyelination and muscle wasting. CLZ-2002, an allogeneic Schwann cell-like product derived from human tonsillar mesenchymal stem cells, has been developed as a regenerative therapy and investigated in CMT1 patients. A Phase 1, open-label, dose-escalation clinical trial was performed in nine patients with genetically diagnosed CMT1 (five with CMT1A, four with CMT1B). Participants were allocated to three dosing cohorts: 6 million (G1), 12 million (G2), or 24 million cells (G3). CLZ-2002 was delivered as a single intramuscular injection into the lower limbs. The primary objective was to assess safety and tolerability. Exploratory endpoints included Charcot-Marie-Tooth Neuropathy Score version 2 (CMTNSv2), Overall Neuropathy Limitation Score-leg (ONLS-leg), Functional Disability Score (FDS), electrophysiology, MRI, and circulating biomarkers. No drug-related adverse reactions, serious adverse events, or dose-limiting toxicities occurred. Four participants experienced a total of five grade 1-2 treatment-emergent adverse events. By Week 24, improvements relative to baseline were noted in CMTNSv2 and ONLS-leg. Biomarker levels of NCAM1 and GDF15 declined at Week 4 but returned toward baseline by Week 24, reflecting the observed clinical trends. A single intramuscular dose of CLZ-2002 of up to 24 million cells was safe and well-tolerated in CMT1 patients. Exploratory efficacy assessments suggested possible clinical benefit, warranting continued investigation of CLZ-2002 in larger, controlled study populations.
Open article ↗
2026-07-14 | HDAC6 inhibition alleviates mitochondrial trafficking in novel models of Charcot-Marie-Tooth Disease Type 2A.
Charcot-Marie-Tooth Disease (CMT) is a group of inherited progressive conditions affecting distal motor and sensory neurons, leading to muscle weakness, pain and loss of sensation in limbs. CMT type 2A (CMT2A) is the most common form of axonal CMT and is associated with a more severe clinical manifestation. However, there are no treatments currently available. To investigate disease mechanisms and facilitate treatment discovery, we developed an in vitro model for CMT2A by introducing the patient-specific MFN2R94Q/+ variant into human embryonic stem cells (hESCs). Isogenic variant and wild-type hESCs differentiated to spinal motor neurons with similar efficiency and gave rise to functional motor neurons in vitro. However, MFN2R94Q/+ spinal motor neurons displayed impaired mitochondrial trafficking, resulting in altered distribution of mitochondria in axons. Unbiased quantitative proteomic profiling of the endogenous MFN2 interactome revealed dose-dependent remodelling by the R94Q variant across 412 proteins, highlighting candidate mechanisms in disease pathology. Importantly, we showed that mitochondrial trafficking defects could be alleviated by treatment with an HDAC6 inhibitor. Chemical inhibition of HDAC6 also rescued the motor phenotype in a zebrafish CMT2A model. Taken together, our study reveals a variant-specific insight into CMT2A disease mechanisms and confirms HDAC6 as a promising target for further therapeutic development.
Open article ↗
2026-07-13 | Neuropathy-Associated HSPB1 Mutant Impairs Neuronal Mechanoadaptation and Axonal Regeneration.
The small heat shock protein HSPB1 is a ubiquitously expressed mechanoresponsive chaperone essential for cytoskeletal remodeling under mechanical load. Mutations in HSPB1, including S135F, cause Charcot-Marie-Tooth (CMT) peripheral neuropathy, yet the mechanisms underlying the selective vulnerability of peripheral nerves remain enigmatic. Here we demonstrate that substrate stiffness is a critical determinant of HSPB1S135F-mediated neurodegeneration. Using stiffness-tunable polydimethylsiloxane (PDMS) substrates (1 kPa, 10 kPa, 2 MPa) and uniaxial cyclic stretch, we show that primary dorsal root ganglia (DRG) neurons and SH-SY5Y cells expressing HSPB1S135F exhibit profound deficits in mechanoadaptation. On compliant substrates (10 kPa), HSPB1S135F causes stretch-induced axon fragmentation and neuronal death, whereas HSPB1WT confers robust neuroprotection. HSPB1S135F also disrupts stiffness-directed neuritogenesis in differentiated SH-SY5Y cells: HSPB1WT-expressing cells show optimal axonal outgrowth and βIII-tubulin expression on 10 kPa substrates mimicking muscle tissue stiffness, while HSPB1S135F mutants display disorganized focal adhesions and complete differentiation failure. Mechanistically, we uncover that HSPB1S135F dysregulates stage-specific transglutaminase (TGase) expression-insufficient TGase during early neuritogenesis impairs filopodia stabilization, whereas aberrant TGase persistence at late stages constrains axon extension. Our findings establish HSPB1 as a biomechanical sensor that integrates ECM stiffness signals to coordinate peripheral nerve regeneration, and identify defective mechanoadaptation as a previously unrecognized pathomechanism in CMT. These results open new avenues for stiffness-targeted therapeutic strategies in peripheral neuropathy.
Open article ↗
2026-07-09 | Onion-Bulb Nerve Roots: An Imaging Clue to Charcot-Marie-Tooth Disease Type 1D
An abstract is not available for this content so a preview has been provided. Please use the Get access link above for information on how to access this content.
Open article ↗
