Association of age at onset in Huntington disease with functional promoter variations in NPY and NPY2R.

Huntingtondisease(HD)iscausedbytheexpansionofaCAG 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 ,a ndNPY5R) may explain some of the variation in AOofHDmotormanifestations,inacomprehensivecohortof 487 German HD patients. We found modest association of the AO with two NPY promoter variations and a highly significant associationwithaNPY2R 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. Key message & Promoter SNPs in NPY and NPY2R explain variation in motor AO of HD & High-expression NPY2R genotypes were associated with later AO in HD & NPY2R activation has a protective effect against mutant htt-induced cell death