Training Group:

Integrative Neuroscience

Mentor / Lab:

Jean-Christophe Rochet

Research Profile:

Parkinson’s disease (PD) is a progressive neurodegenerative disorder for which there are no disease-modifying treatments. Neuropathological hallmarks of PD include the loss of dopaminergic neurons and the formation of cytoplasmic inclusions enriched with aggregated forms of the presynaptic protein alpha-synuclein (aSyn), known as Lewy bodies and Lewy neurites. Although dopaminergic therapies remain the gold standard in PD treatment, current therapeutic approaches only provide symptomatic relief and cannot reverse the degeneration of dopaminergic neurons. Accordingly, there is a high demand for identifying new agents that could serve as disease-modifying therapies. Misfolded aSyn can propagate from cell to cell, and widespread deposition of aSyn aggregates is observed in PD brains. aSyn oligomers and aggregates are toxic, inducing mitochondrial dysfunction, endoplasmic reticulum (ER) stress, and impairment of the autophagy-lysosomal pathway (ALP), ultimately resulting in neuronal death. We are working on cellular models with aSyn aggregate-induced neuropathology, which are critical for understanding the formation and spread of aggregates and testing the efficacy of drugs in rescuing disrupted cellular pathways. We are also focusing on post-translational modifications (PTMs), which are thought to play an important role in modulating aSyn aggregation associated with synucleinopathy disorders. Two high priorities in the synucleinopathy field are to understand how different combinations of aSyn PTMs affect the protein’s aggregation, and how the binding properties of antibodies specific for modified forms of aSyn are influenced by PTMs located near the target epitope (referred to here as ‘neighboring PTMs’). The highly acidic C-terminal domain of aSyn, a region that affects the protein’s secondary structure, contains serine and tyrosine residues that are known to be phosphorylated in human and rodent brain. The most studied aSyn PTM is the phosphorylated form of residue S129. pS129-aSyn has been widely used as a marker for aSyn inclusion formation and was shown to increase in both cellular and animal models of PD. Antibodies are important biochemical tools to detect and quantify aSyn variants phosphorylated on S129 as well as other residues, in the context of both histological analyses of brain pathology and assays of disease biomarkers.

About Me:

When outside of the lab, I enjoy hiking and eating good food!