Scientific Publications Database

Article Title: Dystonin-A3 upregulation is responsible for maintenance of tubulin acetylation in a less severe dystonia musculorum mouse model for hereditary sensory and autonomic neuropathy type VI
Authors: Lynch-Godrei, Anisha; De Repentigny, Yves; Gagnon, Sabrina; My Tran Trung; Kothary, Rashmi
Journal: HUMAN MOLECULAR GENETICS Volume 27 Issue 20
Date of Publication:2018
Abstract:
Hereditary sensory and autonomic neuropathy type VI (HSAN-VI) is a recessive human disease that arises from mutations in the dystonin gene (DST; also known as Bullous pemphigoid antigen 1 gene). A milder form of HSAN-VI was recently described, resulting from loss of a single dystonin isoform (DST-A2). Similarly, mutations in the mouse dystonin gene (Dst) result in severe sensory neuropathy, dystonia musculorum (Dst(dt)). Two Dst(dt) alleles, Dst(dt-Tg4) and Dst(dt-27J), differ in the severity of disease. The less severe Dst(dt-Tg4) mice have disrupted expression of Dst-A1 and -A2 isoforms, while the more severe Dst(dt-27J) allele affects Dst-A1, -A2 and -A3 isoforms. As dystonin is a cytoskeletal-linker protein, we evaluated microtubule network integrity within sensory neurons from Dst(dt-Tg4) and Dst(dt-27J )mice. There is a significant reduction in tubulin acetylation in Dst(dt-27J) indicative of microtubule instability and severe microtubule disorganization within sensory axons. However, Dst(dt-Tg4) mice have no change in tubulin acetylation, and microtubule organization was only mildly impaired. Thus, microtubule instability is not central to initiation of Dst(dt) pathogenesis, though it may contribute to disease severity. Maintenance of microtubule stability in Dst(dt-Tg4) dorsal root ganglia could be attributed to an upregulation in Dst-A3 expression as a compensation for the absence of Dst-A1 and -A2 in Dst(dt-Tg4) sensory neurons. Indeed, knockdown of Dst-A3 in these neurons resulted in a decrease in tubulin acetylation. These findings shed light on the possible compensatory role of dystonin isoforms within HSAN-VI, which might explain the heterogeneity in symptoms within the reported forms of the 3 disease.