to ethanol-induced acute intoxication and alcohol preference in mice 13-15. Several neuroimaging studies have demonstrated that the uptake of acetate is significantly increased in the cerebellum and other brain areas after ethanol consumption in people with alcohol use disorder 14,16. The cerebellum is a primary brain region involved in alcohol metabolism and alcohol motor impairment. However, recent studies provide strong evidence for cerebellar contributions to non-motor functions such as cognition, language, emotions and social behaviours 17-19. The cerebellum also plays a role in many clinical neurological conditions, including attention deficit hyperactivity disorder, schizophrenia, bipolar disorder, major depressive disorder and anxiety disorders 20-22. Relative to the most frequently investigated brain regions, for example, the amygdala and basal ganglia, the cerebellum has been largely overlooked regarding its impact on neurological mechanisms underlying alcohol use disorder. Nevertheless, it remains unclear whether there is a central target that mediates ethanol-derived acetate production and acetate-induced behaviours. Specifically, we have only limited knowledge about the possible role of brain ALDH2 in alcohol metabolism and alcohol intoxication. One major barrier to our understanding of brain ALDH2 is a lack of specific approaches to distinguish between central and peripheral ALDH2-mediated

Nemo-like kinase (NLK), an evolutionarily conserved serine/threonine kinase, is highly expressed in the brain, but its function in the adult brain remains not well understood. In this study, we identify NLK as an interactor of huntingtin protein (HTT). We report that NLK levels are significantly decreased in HD human brain and HD models. Importantly, overexpression of NLK in the striatum attenuates brain atrophy, preserves striatal DARPP32 levels and reduces mutant HTT (mHTT) aggregation in HD mice. In contrast, genetic reduction of NLK exacerbates brain atrophy and loss of DARPP32 in HD mice. Moreover, we demonstrate that NLK lowers mHTT levels in a kinase activity-dependent manner, while having no significant effect on normal HTT protein levels in mouse striatal cells, human cells and HD mouse models. The NLK-mediated lowering of mHTT is associated with enhanced phosphorylation of mHTT. Phosphorylation defective mutation of serine at amino acid 120 (S120) abolishes the mHTT-lowering effect of NLK, suggesting that S120 phosphorylation is an important step in the NLK-mediated lowering of mHTT. A further mechanistic study suggests that NLK promotes mHTT ubiquitination and degradation via the proteasome pathway. Taken together, our results indicate a protective role of NLK in HD and reveal a new molecular target to reduce mHTT levels.

Background: Mutations in