Abstract

Mutations in the SNCA gene encoding α-synuclein (α-syn) underlie familial early-onset Parkinson's disease (PD). Pathological α-syn deposition may commence decades prior to the emergence of cardinal motor symptoms. Long-term investigation of brain and behavioral development in an SNCA-A53T transgenic macaque model offers critical insights into PD progression.In this study, we systematically characterized SNCA-A53T transgenic rhesus monkeys through multimodal assessments. Our results showed that these transgenic monkeys exhibited phosphorylated α-syn aggregation patterns and dopaminergic degeneration resembling PD patients. Progressive motor and cognitive deficits were observed in transgenic monkeys with aging. Polysomnographic analysis revealed REM sleep behavior disorder manifestations in transgenic animals. Four-year longitudinal MRI tracking demonstrated abnormal developmental patterns of cortical surface area alongside thickness and volume alterations. Single-cell transcriptome revealed that astrocyte-specific gene dysregulation and cell loss contribute to brain atrophy in transgenic monkeys. Cortical and subcortical gray matter regions showing volume reduction were functionally associated with behavioral deficits and differentiated transgenic animals from wild-type controls.Collectively, this comprehensive study provides evidence that SNCA-A53T transgenic monkeys recapitulate PD pathophysiology while demonstrating the utility of longitudinal monitoring in genetically engineered nonhuman primates for tracking neurodegenerative disease progression.