Dairy-rich diet triggers hepatic α-synuclein pathology via the liver-brain axis in GBA1-related Parkinson’s disease

Variants in GBA1 represent the most prevalent genetic risk factors for Parkinson's disease (PD), yet how environmental exposures interact with these mutations to drive disease remains unclear. Epidemiological evidence implicates high dairy consumption as a potential modifiable risk factor for PD, but the mechanistic basis remains elusive. Here, we identify hepatic deposition of phosphorylated α-synuclein (pα-syn) in two PD patients carrying the pathogenic GBA1 L444P variant with histories of excessive dairy intake. Using Gba1^L444P/+ mice, we demonstrate that a dairy-rich diet enriched in calcium and casein could induce pathological α-syn aggregation within Kupffer cells (KCs) of the liver. Proteomic profiling reveals that this diet triggers mitochondrial oxidative stress and aggravates GBA1 mutation-induced autophagy defects in KCs, creating a permissive environment for α-synucleinopathy. Notably, hepatic pα-syn pathology propagates to discrete brain regions, including the dorsal nucleus of the vagus nerve, substantia nigra, striatum, and prefrontal cortex, leading to both motor and cognitive impairments. Surgical disruption of liver-brain communication via liver transplantation or hepatic denervation can postpone cerebral pα-syn deposition, confirming a neural conduit for disease transmission. These findings establish the liver as a novel origin site for α-syn pathology in a genetically susceptible context, and define a previously unrecognized liver-brain axis in PD pathogenesis. Our work highlights the interplay between environmental and genetic factors in shaping α-syn dynamics and uncovers potential targets for early intervention in PD.