A microbiome quantitative trait locus in SLC39A8 modulates disease severity in synucleinopathy-induced models of Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by motor deficits, dopaminergic neuron loss, and α-synuclein (α-syn) aggregation. While rare mutations underlie familial PD, around 85% of cases are idiopathic. Emerging evidence implicates common genetic variants and the gut microbiome in PD risk, but their interaction has not been studied. We previously demonstrated that the PD-protective SLC39A8 variant rs13107325 (human A391T, corresponding to A393T in mouse) is associated with microbial compositional shifts in humans and reshapes the microbiome in SLC39A8 A393T knock-in mice. Here, we test whether this SNP modifies PD phenotypes in two α-synucleinopathy mouse models. In the human α-synuclein overexpression model, A393T carrier mice show reduced motor deficits, consistent with a protective role. However, in the α-synuclein preformed fibril (PFF) injection model, A393T carriers exhibit worsened motor deficits, increased dopaminergic terminal loss, and enhanced α-synuclein pathology spread. SNP- and model-specific microbiome changes correlated with motor outcomes. These included enrichment of Lactobacillus and Lactobacillaceae HT002 genera in A393T carriers with α-synuclein overexpression, and enrichment of Erysipelatoclostridium in PFF-injected A393T carriers. These findings suggest that SLC39A8 A393T-induced microbiome alterations are associated with differential disease outcomes depending on context. Our results are consistent with a model in which susceptibility gene SNPs may influence PD progression via the gut microbiome, though direct causal effects remain to be tested.