Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3

Li Zeng; Bo Wang; Sean A. Merillat; Eiko N. Minakawa; Matthew D. Perkins; Biswarathan Ramani; Sara J. Tallaksen-Greene; Maria do Carmo Costa; Roger L. Albin; Henry L. Paulson

Neurobiology of Disease (Oct 2015)

Differential recruitment of UBQLN2 to nuclear inclusions in the polyglutamine diseases HD and SCA3

Li Zeng,
Bo Wang,
Sean A. Merillat,
Eiko N. Minakawa,
Matthew D. Perkins,
Biswarathan Ramani,
Sara J. Tallaksen-Greene,
Maria do Carmo Costa,
Roger L. Albin,
Henry L. Paulson

Affiliations

Li Zeng: Department of Neurology, University of Michigan, Ann Arbor, MI, USA
Bo Wang: Department of Neurology, University of Michigan, Ann Arbor, MI, USA
Sean A. Merillat: Department of Neurology, University of Michigan, Ann Arbor, MI, USA
Eiko N. Minakawa: Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan
Matthew D. Perkins: Michigan Brain Bank, University of Michigan, Ann Arbor, MI, USA
Biswarathan Ramani: Department of Neurology, University of Michigan, Ann Arbor, MI, USA
Sara J. Tallaksen-Greene: Department of Neurology, University of Michigan, Ann Arbor, MI, USA
Maria do Carmo Costa: Department of Neurology, University of Michigan, Ann Arbor, MI, USA
Roger L. Albin: Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Geriatrics Research Education and Clinical Center, VAAAHS, Ann Arbor, MI, USA
Henry L. Paulson: Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Corresponding author at: Department of Neurology, University of Michigan, 109 Zina Pitcher Place, A. Alfred Taubman Biomedical Science Research Building, Ann Arbor, MI 48109, USA.

Journal volume & issue: Vol. 82
pp. 281 – 288

Abstract

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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.

Published in Neurobiology of Disease

ISSN: 0969-9961 (Print); 1095-953X (Online)
Publisher: Elsevier
Country of publisher: United States
LCC subjects: Medicine: Internal medicine: Neurosciences. Biological psychiatry. Neuropsychiatry
Website: https://www.journals.elsevier.com/neurobiology-of-disease

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