HDAC6 Inhibitors Rescued the Defective Axonal Mitochondrial Movement in Motor Neurons Derived from the Induced Pluripotent Stem Cells of Peripheral Neuropathy Patients with HSPB1 Mutation

Abstract

The Charcot-Marie-Tooth disease 2F (CMT2F) and distal hereditary motor neuropathy 2B (dHMN2B) are caused by autosomal dominantly inherited mutations of the heat shock 27 kDa protein 1 (HSPB1) gene and there are no specific therapies available yet. Here, we assessed the potential therapeutic effect of HDAC6 inhibitors on peripheral neuropathy with HSPB1 mutation using in vitro model of motor neurons derived from induced pluripotent stem cells (iPSCs) of CMT2F and dHMN2B patients. The absolute velocity of mitochondrial movements and the percentage of moving mitochondria in axons were lower both in CMT2F-motor neurons and in dHMN2B-motor neurons than those in controls, and the severity of the defective mitochondrial movement was different between the two disease models. CMT2F-motor neurons and dHMN2B-motor neurons also showed reduced α-tubulin acetylation compared with controls. The newly developed HDAC6 inhibitors, CHEMICAL X4 and CHEMICAL X9, increased acetylation of α-tubulin and reversed axonal movement defects of mitochondria in CMT2F-motor neurons and dHMN2B-motor neurons. Our results suggest that the neurons derived from patient-specific iPSCs can be used in drug screening including HDAC6 inhibitors targeting peripheral neuropathy.

Excessive tubulin polyglutamylation causes neurodegeneration and perturbs neuronal transport

“…Tubulin acetylation for instance had previously been linked to neurodegenerative disorders such as Huntington's disease (Dompierre et al, 2007), Charcot-Marie-Tooth disease (d'Ydewalle et al, 2011;Kim et al, 2016), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (Godena et al, 2014). Tubulin acetylation for instance had previously been linked to neurodegenerative disorders such as Huntington's disease (Dompierre et al, 2007), Charcot-Marie-Tooth disease (d'Ydewalle et al, 2011;Kim et al, 2016), amyotrophic lateral sclerosis (ALS), and Parkinson's disease (Godena et al, 2014).…”

Decreased ceramide underlies mitochondrial dysfunction in Charcot‐Marie‐Tooth 2F

“…Evidence suggests that Hsp27 restricts cell death by reducing protein aggregation or other pathologic mechanisms seen in Alzheimer's, Huntington's, and Parkinson's diseases and amylotrophic lateral sclerosis (ALS) (12,13). However, the pathogenesis of Hsp27 in CMT2F remains unknown but is thought to be a result of defects in axonal transport of mitochondria (14).…”

Insights into the pathogenesis of ATP1A1‐related CMT disease using patient‐specific iPSCs

“…3,4 iPSC-derived neurons have been also developed from axonal CMT patients carrying NEFL, 5,6 MFN2, 5,7 and HSPB1 mutations. 8 The results have shown that, unlike iPSCs-derived cells from demyelinating CMT patients, the neuronal lines from axonal CMT patients develop distinct phenotypes, probably due to the defects of specific genes. Recently, we have described a novel axonal CMT genotype related to mutations in the gene coding the α1 subunit of the sodium (Na + )/ potassium (K + )-ATPase (ATP1A1).…”

“…Notably, the iPSC‐derived neural crest cells, which are Schwann cell (SC) progenitors, exhibit a common defect in differentiating to myelinating SC . iPSC‐derived neurons have been also developed from axonal CMT patients carrying NEFL , MFN2 , and HSPB1 mutations . The results have shown that, unlike iPSCs‐derived cells from demyelinating CMT patients, the neuronal lines from axonal CMT patients develop distinct phenotypes, probably due to the defects of specific genes.…”