Deletion of Small Ubiquitin-like Modifier-1 Attenuates Behavioral and Anatomical Deficits by Enhancing Functional Autophagic Activities in Huntington Disease

Abstract

Mutant HTT (mHTT) associated with Huntington disease (HD) affects the central nervous system by prominent atrophy in the striatum and promotes psychiatric, cognitive, and choreiform movements, although the exact mechanism remains obscure. Previous studies have shown that SUMO1 (Small Ubiquitin-like Modifier-1) modification of mHTT promotes cellular toxicity, but the in vivo role and functions of SUMO1 in HD pathogenesis are unclear. Here, we report that SUMO1 deletion in Q175DN HD-het knock-in mice (HD mice) prevented age-dependent HD-like motor and neurological impairments and suppressed the striatal atrophy and inflammatory response. SUMO1 deletion caused a drastic reduction in soluble mHtt levels and nuclear and extracellular mHtt inclusions, while increasing cytoplasmic inclusions in the striatum of HD mice. SUMO1 deletion also enhanced autophagic activity, characterized by augmented interactions between mHTT inclusions and a lysosomal marker (LAMP1), increased LC3B/LAMP1 interaction, and decreased sequestosome-1 (p62) and mHTT and diminished p62/LAMP1 interactions in DARPP-32 positive medium spiny neurons (MSNs) in HD mice. Depletion of SUMO1 in an HD cell model also diminished the mHtt levels and enhanced autophagy flux. In addition, the SUMOylation inhibitor ginkgolic acid strongly enhanced autophagy and diminished mHTT levels in human HD fibroblasts. These results indicate that SUMO is a critical therapeutic target in HD and that blocking SUMO may ameliorate HD pathogenesis by improving autophagy activities.

Rhes Deletion Prevents Age-Dependent Selective Motor Deficits and Reduces Phosphorylation of S6K in Huntington Disease Hdh150Q(CAG) Knock-In Mice

“…Rhes binds to Nix and promotes selective autophagy (mitophagy) [44] . Moreover, we showed that SUMO regulates mTORC1 and autophagy signaling and prevents HD-related deficits in Q175DN-KI model that show enhanced mTORC1 activity [54,73,74] . Previous pharmacological studies with mTORC1 inhibition showed beneficial effects in HD models [54,75] .…”