Ubiquitin-modifying enzymes in Huntington's disease

Abstract

Huntington's disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the N-terminus of the HTT gene. The CAG repeat expansion translates into a polyglutamine expansion in the mutant HTT (mHTT) protein, resulting in intracellular aggregation and neurotoxicity. Lowering the mHTT protein by reducing synthesis or improving degradation would delay or prevent the onset of HD, and the ubiquitin-proteasome system (UPS) could be an important pathway to clear the mHTT proteins prior to aggregation. The UPS is not impaired in HD, and proteasomes can degrade mHTT entirely when HTT is targeted for degradation. However, the mHTT protein is differently ubiquitinated when compared to wild-type HTT (wtHTT), suggesting that the polyQ expansion affects interaction with (de) ubiquitinating enzymes and subsequent targeting for degradation. The soluble mHTT protein is associated with several ubiquitin-modifying enzymes, and various ubiquitin-modifying enzymes have been identified that are linked to Huntington's disease, either by improving mHTT turnover or affecting overall homeostasis. Here we describe their potential mechanism of action toward improved mHTT targeting towards the proteostasis machinery.

Keywords: Huntington’s disease; deubiquitinating enzyme; huntingtin; ligase; neurodegenerative disease; proteasome; proteostasis; ubiquitin.

FIGURE 1

Method of action of enzyme classes involved in the ubiquitination pathway. The classes of E1 ubiquitin-activating enzymes are shown (grey), four classes of E2 ubiquitin-conjugating enzymes (yellow), and four families of E3 ubiquitin ligases (blue) and deubiquitinating enzymes (pink). Ubiquitination sites K6, K9 and K15 at the N-terminus of HTT are shown at the right.

FIGURE 2

Ubiquitin-modifying enzymes that affect mHTT protein levels, solubilization, oligomerization, aggregation, degradation and mHTT-induced cellular stress. E1 enzymes are shown in grey, E2 enzymes are shown in yellow, E3 enzymes are shown in blue, DUBs are shown in pink. Green arrows: enzymes reduce mHTT levels, red arrows: enzymes increase mHTT levels, grey arrows: enzymes affect a process but not mHTT levels.