title: Microtubule stability, Golgi organization, and transport flux require dystonin-a2-MAP1B interaction.
abstract: Loss of function of dystonin cytoskeletal linker proteins causes neurodegeneration in dystonia musculorum (dt) mutant mice. Although much investigation has focused on understanding dt pathology, the diverse cellular functions of dystonin isoforms remain poorly characterized. In this paper, we highlight novel functions of the dystonin-a2 isoform in mediating microtubule (MT) stability, Golgi organization, and flux through the secretory pathway. Using dystonin mutant mice combined with isoform-specific loss-of-function analysis, we found dystonin-a2 bound to MT-associated protein 1B (MAP1B) in the centrosomal region, where it maintained MT acetylation. In dt neurons, absence of the MAP1B-dystonin-a2 interaction resulted in altered MAP1B perikaryal localization, leading to MT deacetylation and instability. Deacetylated MT accumulation resulted in Golgi fragmentation and prevented anterograde trafficking via motor proteins. Maintenance of MT acetylation through trichostatin A administration or MAP1B overexpression mitigated the observed defect. These cellular aberrations are apparent in prephenotype dorsal root ganglia and primary sensory neurons from dt mice, suggesting they are causal in the disorder.
authors.affiliation: Ottawa Hospital Research Institute, Ottawa, Ontario K1H 8L6, Canada.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Ryan
authors.forename: Kunal
authors.initials: K
authors.lastname: Bhanot
authors.forename: Andrew
authors.initials: A
authors.lastname: Ferrier
authors.forename: Yves
authors.initials: Y
authors.lastname: De Repentigny
authors.forename: Alphonse
authors.initials: A
authors.lastname: Chu
authors.forename: Alexandre
authors.initials: A
authors.lastname: Blais
authors.forename: Rashmi
authors.initials: R
authors.lastname: Kothary
mesh_terms: D000107:Acetylation; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D004421:Dystonia / Q000235:genetics / Q000378:metabolism; D000071821:Dystonin; D005727:Ganglia, Spinal / Q000378:metabolism; D006056:Golgi Apparatus / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D014162:Transfection
chemical_list: D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C095667:Dst protein, mouse; D000071821:Dystonin; D008869:Microtubule-Associated Proteins; D009419:Nerve Tissue Proteins; D020033:Protein Isoforms; C085284:microtubule-associated protein 1B