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Huntington disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the HTT gene. Although the variation in age at onset (AO) is partly explained by the lengths of the expanded repeats, the unexplained variation is highly heritable, emphasizing the role of the so-called genetic background on disease expression. Neuropeptide Y (NPY) has been implicated in the modulation of neuroprotection, neurogenesis, and neuroinflammation. Therefore, the aim of the present study was to analyze different single nucleotide polymorphisms (SNPs) in order to test the possibility that genetic variation in NPY or three of its receptor genes (NPY1R, NPY2R, and NPY5R) may explain some of the variation in AO of HD motor manifestations, in a comprehensive cohort of 487 German HD patients. We found modest association of the AO with two NPY promoter variations and a highly significant association with a NPY2R promoter SNP (rs2234759; p = 0.0004). Investigating the functional impact of rs2234759 by luciferase assays revealed that the high-expression NPY2R genotypes were associated with later AO in HD. Additionally, treatment of PC12 cells expressing mutant huntingtin (htt) exon 1 with NPY and the NPY2R agonist NPY(3-36) has a protective effect against mutant htt-induced cell death. Thus, NPY might act through Y2 receptors to slow down the course of HD, and hence, this peptide could be of interest as a possible therapeutic agent.

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BackgroundNeuropeptide Y (NPY) is a potent neuromodulator that is expressed throughout the central nervous system. The sparing and persistence increase in NPY-expressing striatal interneurons with advancing disease have been implicated to correlate with striatal pathology in both Huntington’s disease (HD) patients and animal models of HD. However, the potential roles of intense expression of NPY in HD pathology still remain under-explored.AimsTo investigate whether activation of NPY-Y2 receptor using NPY and selective Y2 receptor ligands could ameliorate behavioural deficits and neuropathology in R6/2 mouse model of HD.Methods/techniquesNPY and selective Y2 receptor agonist NPY13-36 were intranasally administered to R6/2 mice, five days in a week, beginning from 4 weeks of age until 12 weeks of age. In the second study, R6/2 mice received daily intraperitoneal administration of selective non-peptide Y2 receptor antagonist (SF-31) to selectively block Y2 receptor.Results/outcomeIntranasal application of NPY showed significant increase in rotarod performance compared to saline and SF-31 treated R6/2 mice (pp < 0.05 and **p < 0.01 at 8 and 12 weeks of age respectively, n = 10). However, treatment with NPY13-36 showed a clear trend towards increased rotarod performance at 12 weeks of age compared with the saline and SF-31 treated R6/2 mice but the difference did not reach significance. Also, we found no statistically significant difference in body weight loss between the groups, contrasting with previous data obtained with single intracerebroventricular (ICV) injection of NPY in R6/2 mice. Furthermore, intranasal application NPY or NPY13-36 led to decrease in mutant Huntingtin (Htt) aggregation and mediated increase in dopamine-and cAMP regulated phosphoprotein (DARPP-32) and brain derived neurotrophic factor (BDNF) levels. Additionally, we found that NPY and NPY13-36 attenuate microglial activation and expression of interleukin-1beta mRNA expression.ConclusionTaken together, our findings suggest that targeting NPY-Y2 receptor might be a potential neuroprotective therapy for HD and other neurodegenerative diseases.