title: Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3.
abstract: Accumulation of mutant polyglutamine proteins in intraneuronal inclusions is a hallmark of polyglutamine diseases. Impairment of protein clearance systems and sequestration of clearance-related proteins into inclusions occur in many protein folding diseases, including polyglutamine diseases. The ubiquitin-binding and proteasome adaptor protein UBQLN2 participates in protein homeostasis and localizes to inclusions in various neurodegenerative diseases. Employing mouse models and human brain tissue of Huntington's disease (HD) and spinocerebellar ataxia type 3 (SCA3), we show that UBQLN2 is selectively recruited to inclusions in HD but not SCA3. Consistent with this result, in a cell-based system mutant HTT interacts with UBQLN2 through the UBA domain while the SCA3 disease protein ATXN3, a deubiquitinating enzyme, does not interact with UBQLN2. Differential recruitment of UBQLN2 to aggregates in HD and SCA3 underscores the heterogeneity of inclusions in polyglutamine diseases and suggests that components of neuronal protein quality control may be differentially perturbed in distinct polyQ diseases.
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Zeng
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Sean A
authors.initials: SA
authors.lastname: Merillat
authors.affiliation: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan.
authors.forename: Eiko N
authors.initials: EN
authors.lastname: Minakawa
authors.affiliation: Michigan Brain Bank, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Perkins
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Biswarathan
authors.initials: B
authors.lastname: Ramani
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Tallaksen-Greene
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
authors.forename: Maria do Carmo
authors.initials: MDC
authors.lastname: Costa
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Geriatrics Research Education and Clinical Center, VAAAHS, Ann Arbor, MI, USA.
authors.forename: Roger L
authors.initials: RL
authors.lastname: Albin
authors.affiliation: Department of Neurology, University of Michigan, Ann Arbor, MI, USA. Electronic address: henryp@umich.edu.
authors.forename: Henry L
authors.initials: HL
authors.lastname: Paulson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000067699:Ataxin-3 / Q000235:genetics / Q000378:metabolism; D000071183:Autophagy-Related Proteins; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D018450:Disease Progression; D057809:HEK293 Cells; D006801:Humans; D000071058:Huntingtin Protein; D006816:Huntington Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045586:Intranuclear Inclusion Bodies / Q000378:metabolism* / Q000473:pathology; D017827:Machado-Joseph Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008822:Mice, Transgenic; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D014452:Ubiquitins / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D033942:Adaptor Proteins, Vesicular Transport; D000071183:Autophagy-Related Proteins; D018797:Cell Cycle Proteins; C086055:HTT protein, human; D000071058:Huntingtin Protein; D009419:Nerve Tissue Proteins; D012097:Repressor Proteins; C405662:UBQLN2 protein, human; C538988:UBQLN2 protein, mouse; D014452:Ubiquitins; C092341:ATXN3 protein, human; D000067699:Ataxin-3
keywords: Huntington's disease; Polyglutamine; SCA3; UBA; UBL; UBQLN2