Neuronal dystonin isoform 2 is a mediator of endoplasmic reticulum structure and function

Scott D. Ryan, Andrew Ferrier, Tadasu Sato, Ryan W. O'Meara, Yves De Repentigny, Susan X. Jiang, Sheng T. Hou, Rashmi Kothary

Research output: Contribution to journalArticlepeer-review

34 Citations (Scopus)


Dystonin/Bpag1 is a cytoskeletal linker protein whose loss of function in dystonia musculorum (dt) mice results in hereditary sensory neuropathy. Although loss of expression of neuronal dystonin isoforms (dystonin-a1/dystonin-a2) is sufficient to cause dt pathogenesis, the diverging function of each isoform and what pathological mechanisms are activated upon their loss remains unclear. Here we show that dt 27 mice manifest ultrastructural defects at the endoplasmic reticulum (ER) in sensory neurons corresponding to in vivo induction of ER stress proteins. ER stress subsequently leads to sensory neurodegeneration through induction of a proapoptotic caspase cascade. dt sensory neurons display neurodegenerative pathologies, including Ca 2+ dyshomeostasis, unfolded protein response (UPR) induction, caspase activation, and apoptosis. Isoform-specific loss-of-function analysis attributes these neurodegenerative pathologies to specific loss of dystonin-a2. Inhibition of either UPR or caspase signaling promotes the viability of cells deficient in dystonin. This study provides insight into the mechanism of dt neuropathology and proposes a role for dystonin-a2 as a mediator of normal ER structure and function.

Original languageEnglish
Pages (from-to)553-566
Number of pages14
JournalMolecular Biology of the Cell
Issue number4
Publication statusPublished - 2012 Feb 15


Dive into the research topics of 'Neuronal dystonin isoform 2 is a mediator of endoplasmic reticulum structure and function'. Together they form a unique fingerprint.

Cite this