The ubiquitin conjugating enzyme Ube2W regulates solubility of the Huntington's disease protein, huntingtin

Bo Wang; Li Zeng; Sean A Merillat; Svetlana Fischer; Joseph Ochaba; Leslie M Thompson; Sami J Barmada; Kenneth M Scaglione; Henry L Paulson

doi:10.1016/j.nbd.2017.10.002

The ubiquitin conjugating enzyme Ube2W regulates solubility of the Huntington's disease protein, huntingtin

Neurobiol Dis. 2018 Jan;109(Pt A):127-136. doi: 10.1016/j.nbd.2017.10.002. Epub 2017 Oct 3.

Authors

Bo Wang¹, Li Zeng², Sean A Merillat³, Svetlana Fischer³, Joseph Ochaba⁴, Leslie M Thompson⁴, Sami J Barmada³, Kenneth M Scaglione⁵, Henry L Paulson⁶

Affiliations

¹ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Neuroscience Program, University of Michigan, Ann Arbor, MI 48109, USA; Department of Dermatology, Ruijin Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, China.
² Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Department of Neurology, Sichuan Provincial Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
³ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
⁴ Department of Neurobiology and Behavior, Institute of Memory Impairment and Neurological Disorders, University of California, Irvine, CA 92697, USA; Department of Psychiatry and Human Behavior, Institute of Memory Impairment and Neurological Disorders, University of California, Irvine, CA 92697, USA.
⁵ Neuroscience Research Center and Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
⁶ Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Neuroscience Program, University of Michigan, Ann Arbor, MI 48109, USA. Electronic address: [email protected].

Abstract

Huntington's disease (HD) is caused by a CAG repeat expansion that encodes a polyglutamine (polyQ) expansion in the HD disease protein, huntingtin (HTT). PolyQ expansion promotes misfolding and aggregation of mutant HTT (mHTT) within neurons. The cellular pathways, including ubiquitin-dependent processes, by which mHTT is regulated remain incompletely understood. Ube2W is the only ubiquitin conjugating enzyme (E2) known to ubiquitinate substrates at their amino (N)-termini, likely favoring substrates with disordered N-termini. By virtue of its N-terminal polyQ domain, HTT has an intrinsically disordered amino terminus. In studies employing immortalized cells, primary neurons and a knock-in (KI) mouse model of HD, we tested the effect of Ube2W deficiency on mHTT levels, aggregation and neurotoxicity. In cultured cells, deficiency of Ube2W activity markedly decreases mHTT aggregate formation and increases the level of soluble monomers, while reducing mHTT-induced cytotoxicity. Consistent with this result, the absence of Ube2W in HdhQ200 KI mice significantly increases levels of soluble monomeric mHTT while reducing insoluble oligomeric species. This study sheds light on the potential function of the non-canonical ubiquitin-conjugating enzyme, Ube2W, in this polyQ neurodegenerative disease.

Keywords: Huntingtin; Huntington's disease; Neurodegeneration; Protein misfolding; Ube2W; Ubiquitin-conjugating enzyme; Ubiquitination.

MeSH terms

Animals
Corpus Striatum / enzymology
Corpus Striatum / pathology
Disease Models, Animal
Gene Knock-In Techniques
HEK293 Cells
Humans
Huntingtin Protein / metabolism*
Huntington Disease / enzymology*
Huntington Disease / genetics
Inclusion Bodies / metabolism
Male
Mice, Inbred C57BL
Mice, Knockout
Neurons / enzymology*
Neurons / pathology
Primary Cell Culture
Ubiquitin-Conjugating Enzymes / genetics
Ubiquitin-Conjugating Enzymes / metabolism*

Substances

Htt protein, mouse
Huntingtin Protein
UBE2W protein, mouse
Ubiquitin-Conjugating Enzymes

Abstract

MeSH terms

Substances

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