title: Neuronal dystonin isoform 2 is a mediator of endoplasmic reticulum structure and function.
abstract: 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.
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Ryan
authors.forename: Andrew
authors.initials: A
authors.lastname: Ferrier
authors.forename: Tadasu
authors.initials: T
authors.lastname: Sato
authors.forename: Ryan W
authors.initials: RW
authors.lastname: O'Meara
authors.forename: Yves
authors.initials: Y
authors.lastname: De Repentigny
authors.forename: Susan X
authors.initials: SX
authors.lastname: Jiang
authors.forename: Sheng T
authors.initials: ST
authors.lastname: Hou
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
mesh_terms: D000818:Animals; D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000502:physiology*; D020169:Caspases / Q000096:biosynthesis; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000502:physiology*; D004422:Dystonia Musculorum Deformans / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000071821:Dystonin; D004721:Endoplasmic Reticulum / Q000502:physiology* / Q000648:ultrastructure; D059865:Endoplasmic Reticulum Stress; D004789:Enzyme Activation; D051379:Mice; D008817:Mice, Mutant Strains; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000502:physiology*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D056811:Unfolded Protein Response
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C095667:Dst protein, mouse; D000071821:Dystonin; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; D020169:Caspases; D002118:Calcium