LAUSR

Significance SUMO protein can decorate other proteins via a process called SUMOylation that can regulate toxicity of proteins linked to neurodegenerative diseases. The mutant huntingtin (mHTT) protein in Huntington disease (HD) degenerates nerve cells, and SUMOylation of mHTT makes it more soluble and more toxic to the nerve cells. Here, we show that SUMO deletion in a humanized mouse HD model depletes mHTT and prevents brain shrinkage and behavioral abnormalities. SUMO deletion blocked inflammation and enhanced autophagy, a beneficial cellular degradation pathway. Importantly, ginkgolic acid (GA), a widely used plant supplement that can inhibit SUMOylation, activates autophagy and promotes the degradation of mHTT in human HD cells. Thus, our study indicates GA and analogs might be therapeutically beneficial to HD patients. The CAG expansion of huntingtin (mHTT) associated with Huntington disease (HD) is a ubiquitously expressed gene, yet it prominently damages the striatum and cortex, followed by widespread peripheral defects as the disease progresses. However, the underlying mechanisms of neuronal vulnerability are unclear. 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 knockin 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 mHtt inclusions in the striatum of HD mice. SUMO1 deletion promoted autophagic activity, characterized by augmented interactions between mHtt inclusions and a lysosomal marker (LAMP1), increased LC3B- and LAMP1 interaction, and decreased interaction of sequestosome-1 (p62) and LAMP1 in DARPP-32–positive medium spiny neurons 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 regulating autophagy activities.