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This project asks whether Parkinson’s disease (PD) begins before birth. PD is traditionally viewed as a disorder of aging, yet selective neuronal vulnerability may be programmed decades earlier. SNCA, encoding a-synuclein, is a central PD gene. While misfolded a-synuclein aggregates are a hallmark of PD, its physiological role remains poorly understood. 

Strikingly, a-synuclein is robustly expressed in the embryonic brain, including in immature midbrain dopaminergic (mDA) neurons – the main subtype that later degenerates. Earlier studies showed that a-synuclein deficiency reduces the pool of immature mDA neurons, providing functional precedent for its developmental role. Does early a-synuclein dysfunction program neurons for future vulnerability to diverse stressors?

This project will define a-synuclein’s roles in mDA neuron specification, maturation, and connectivity during embryogenesis, and test whether its loss-of-function creates latent vulnerabilities that increase susceptibility to aging and environmental challenges. Using Snca knockout mice, I will perform spatiotemporal mapping of a-synuclein expression across developmental stages to assess protein localization and mDA lineage identity and fate. Light-sheet microscopy of intact, tissue-cleared embryonic brains will generate 3D reconstructions of mDA populations and their projections. Laser capture microdissection, RNA sequencing, proteomics, and interactome analyses will identify molecular pathways under a-synuclein’s control and candidates driving long-term neuronal resilience or vulnerability.

By linking prenatal molecular and cellular events to selective neuronal loss in PD, this work will challenge prevailing dogma, establish a mechanistic framework for a-synuclein’s developmental functions, and reveal novel targets for early diagnosis and intervention. If confirmed, these findings could redefine PD as a disorder with developmental origins, opening new avenues for prevention and neuroprotection.