Lack of GDAP1 Induces Neuronal Calcium and Mitochondrial Defects in a Knockout Mouse Model of Charcot-Marie-Tooth Neuropathy

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Charcot-Marie-Tooth (CMT) disease is an inherited motor and sensory peripheral neuropathy. Mutations in the GDAP1 gene cause either an axonapathy or an myelinopathy that can be transmitted recessively or dominantly to offspring. GDAP1 is located in the mitochondrial outer membrane and seems to participate in the mitochondrial network dynamics. To investigate the biological and functional consequences of lack of GDAP1 and to gain insight into the pathophysiology of the GDAP1-related neuropathies we have generated a Gdap1 knockout mouse. Characterization of this model revealed that the absence of GDAP1 induces a peripheral neuropathy with loss of motor neurons and abnormal neuromuscular junctions. We also observed defects in embryonic motor neurons and adult dorsal root ganglia sensory neurons derived from affected animals. Specifically, cultured motor neurons showed large and abnormal mitochondria, dilated perinuclear space and endoplasmic reticulum, changes in acetylation of cytoskeletal α-tubulin and calcium depletion. We propose that pathophysiology of GDAP1-associated recessive CMT neuropathy may be the consequence of abnormal calcium homeostasis and changes in the mitochondrial network biology and mitochondria–endoplasmic reticulum interactions. Our findings may be also relevant to understand the role of GDAP1 in relation to other neuropathy-related mitochondrial proteins such as mitofusin 2.

Vyšlo v časopise: Lack of GDAP1 Induces Neuronal Calcium and Mitochondrial Defects in a Knockout Mouse Model of Charcot-Marie-Tooth Neuropathy. PLoS Genet 11(4): e32767. doi:10.1371/journal.pgen.1005115
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1005115

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