From Genes to Virtual Brain: Defining the Pathogenic Mechanisms Promoting Alfa-synuclein Seeding and Spreading in Parkinson's Disease.

Parkinson's disease (PD) is characterized by pathological aggregation and propagation of alpha synuclein, leading to synaptic and mitochondrial dysfunction. Heterozygous mutations in the GBA1 gene represent the strongest genetic risk factor for PD and are associated with earlier onset, faster progression, and increased burden of misfolded alpha synuclein. Experimental evidence suggests that alpha synuclein toxicity may be amplified by its interaction with tau, promoting synergistic neurodegenerative mechanisms; however, in vivo human data on these processes remain limited.

This study aims to define, through a personalized and multimodal approach, how alpha synuclein accumulation and its interaction with tau influence synaptic and mitochondrial dysfunction and brain connectivity across the PD spectrum, from periclinal stages to established disease, with particular focus on the impact of GBA1 mutations. The study includes patients with PD, individuals with idiopathic REM sleep behavior disorder (iRBD), and subjects without PD, both carriers and non carriers of GBA1 mutations.

All participants will undergo comprehensive clinical and neuropsychological assessments to characterize motor, non motor, and cognitive manifestations across disease stages. Blood samples will be collected to define a fluid biomarker profile, including alpha synuclein, tau, markers of synaptic integrity, mitochondrial function, and neurodegeneration. In addition, all participants will undergo multimodal brain MRI, including structural, diffusion weighted, and resting state functional sequences, to evaluate brain structure, white matter integrity, and functional connectivity.

In a subset of participants, a skin biopsy will be performed to generate patient specific induced pluripotent stem cell (hiPSC) derived dopaminergic neurons. These cellular models will be used to investigate neuronal and synaptic function in relation to individual biomarker profiles and genetic background. In parallel, preclinical studies will be conducted in GBA-PD mouse models and wild type mice injected with saline, alpha synuclein or combined alpha synuclein/tau fibrils. Mice will undergo behavioral, in vivo MRI and PET imaging and post mortem assessment of synaptic, axonal and mitochondrial pathology. In addition, a novel alpha synuclein PET tracer, [¹⁸F]Syntacasyn, will undergo preclinical validation.

Multimodal human and animal data will be integrated using advanced statistical and computational approaches to identify vulnerable network hubs and generate subject specific "virtual brain" models of alpha synuclein pathology propagation.