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.

Peripheral sequestration of huntingtin delays neuronal death and depends on N-terminal ubiquitination

“…Of note, lysines 6 and 9 are part of a conserved 17 amino acid N-terminal segment upstream of the polyQ stretch, that plays crucial roles in mHtt oligomerization and bril nucleation (Arndt et al, 2015). It was thus suggested that ubiquitin conjugation at these sites promotes the formation of large, visible mHtt aggregates, which, by sequestering away oligomeric or proto brillar forms of mHtt, decreases proteotoxicity and delays cell death (Van Well et al, 2019; Hakim-Eshed et al, 2020;Ziv and Ciechanover, 2021;Sap et al, 2023). While this interpretation is congruent with the aforementioned protective roles of aggregates, key questions remain open: What are the temporal relationships between mHtt aggregate formation and changes in cytosolic mHtt levels?…”

“…Indeed, mHtt aggregates label strongly when probed with antibodies against ubiquitin and are commonly found in tight association with ubiquitin conjugating / deubiquitinating enzymes, ubiquitin-interacting proteins and proteasomes (e.g. DiFiglia Sap et al, 2023). In line with these ndings, proteomic comparisons of Htt ubiquitination pro les in two separate HD animal models revealed that mHtt, but not wild-type Htt, is selectively ubiquitinated on two lysine residues (K6 and K9) at the N-terminus of mHtt in a segment encoded by HTT exon 1 (Sap et al, 2019;Hakim-Eshed et al, 2020).…”