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

Neurobiology of Disease (Jan 2018)

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

Affiliations

Bo Wang: 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
Li Zeng: 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
Sean A. Merillat: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
Svetlana Fischer: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
Joseph Ochaba: 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
Leslie M. Thompson: 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
Sami J. Barmada: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA
Kenneth M. Scaglione: Neuroscience Research Center and Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Henry L. Paulson: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Neuroscience Program, University of Michigan, Ann Arbor, MI 48109, USA; Corresponding author at: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.

Journal volume & issue: Vol. 109
pp. 127 – 136

Abstract

Read online

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.

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

About the journal

Abstract

Keywords