Deletion of SUMO1 attenuates behavioral and anatomical deficits by regulating autophagic activities in Huntington disease

• DOI: 10.1073/pnas.2107187119
• Publication Date: 2022-01-27T21:05:14Z
• Authors: Uri Nimrod Ramíre...; Manish Sharma; Wuyue Zhou; Neelam Shahani; Srinivasa Subrama...
• Keywords: Pathogenesis; Sequestosome 1; LAMP1

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 progresses. However, underlying mechanisms neuronal vulnerability are unclear. Previous studies have shown that SUMO1 (small ubiquitin-like modifier-1) modification mHtt promotes cellular toxicity, but in vivo role functions HD pathogenesis Here, we report deletion Q175DN HD-het knockin mice (HD mice) prevented age-dependent HD-like motor neurological impairments suppressed striatal atrophy inflammatory response. caused drastic reduction soluble levels nuclear extracellular inclusions while increasing cytoplasmic mice. promoted autophagic activity, characterized augmented interactions between lysosomal marker (LAMP1), increased LC3B- LAMP1 interaction, decreased interaction sequestosome-1 (p62) DARPP-32-positive medium spiny neurons Depletion an cell model also diminished enhanced autophagy flux. In addition, SUMOylation inhibitor ginkgolic acid strongly mHTT human fibroblasts. These results indicate SUMO critical therapeutic target blocking may ameliorate regulating activities.