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

doi:10.1016/j.nbd.2015.06.017

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

Neurobiol Dis. 2015 Oct:82:281-288. doi: 10.1016/j.nbd.2015.06.017. Epub 2015 Jun 30.

Affiliations

¹ Department of Neurology, University of Michigan, Ann Arbor, MI, USA.
² Department of Degenerative Neurological Diseases, National Institute of Neuroscience, National Center of Neurology and Psychiatry (NCNP), Kodaira, Tokyo, Japan.
³ Michigan Brain Bank, University of Michigan, Ann Arbor, MI, USA.
⁴ Department of Neurology, University of Michigan, Ann Arbor, MI, USA; Geriatrics Research Education and Clinical Center, VAAAHS, Ann Arbor, MI, USA.
⁵ Department of Neurology, University of Michigan, Ann Arbor, MI, USA. Electronic address: henryp@umich.edu.

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.

Keywords: Huntington's disease; Polyglutamine; SCA3; UBA; UBL; UBQLN2.

Publication types

Comparative Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport / genetics
Adaptor Proteins, Vesicular Transport / metabolism*
Animals
Ataxin-3 / genetics
Ataxin-3 / metabolism
Autophagy-Related Proteins
Brain / metabolism*
Brain / pathology
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism*
Disease Models, Animal
Disease Progression
HEK293 Cells
Humans
Huntingtin Protein
Huntington Disease / genetics
Huntington Disease / metabolism*
Huntington Disease / pathology
Intranuclear Inclusion Bodies / metabolism*
Intranuclear Inclusion Bodies / pathology
Machado-Joseph Disease / genetics
Machado-Joseph Disease / metabolism*
Machado-Joseph Disease / pathology
Mice, Transgenic
Mutation
Nerve Tissue Proteins / genetics
Nerve Tissue Proteins / metabolism
Repressor Proteins / genetics
Repressor Proteins / metabolism
Ubiquitins / genetics
Ubiquitins / metabolism*

Substances

Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport
Autophagy-Related Proteins
Cell Cycle Proteins
HTT protein, human
Huntingtin Protein
Nerve Tissue Proteins
Repressor Proteins
UBQLN2 protein, human
UBQLN2 protein, mouse
Ubiquitins
ATXN3 protein, human
Ataxin-3

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

Authors

Affiliations

Abstract

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MeSH terms

Substances

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