Harvard Catalyst Profiles

a-Synuclein (aS), a product of SNCA, is an abundant presynaptic protein that regulates neurotransmission. aS orchestrates neurotransmitter release by synaptic vesicle cycling, SNARE assembly, clustering of synaptic vesicles, and dilation of the fusion pore during exocytosis. aS is also a key protein implicated in a broad class of neurodegenerative disorders termed “synucleinopathies”, which encompasses Parkinson’s disease (PD), dementia with Lewy Bodies (DLB), and Multiple System Atrophy (MSA). The pathological aS deposits, Lewy Bodies (LBs), and Lewy Neurites (LNs) are also documented in Alzheimer’s disease and related forms of dementia, thus extending the list of dementias with LB pathology. DLB and PD with dementia (PDD) are collectively termed Lewy Body Dementia (LBD). Remarkably, about 90% of aS in the LB and LN is acknowledged to be present in its serine-129 phosphorylated form (pS129). Therefore, pS129 is widely used as a surrogate marker for pathology. However, we recently demonstrated that physiological pS129, triggered by neuronal activity, positively regulates synaptic transmission. These unexpected and intriguing results raise the critical question of whether normal and abnormal pS129 can be distinguished. Given our expertise in studying normal pS129, we are in the unique position to test whether the properties of normal pS129 are different from abnormal pS129. This medical student project will a) help distinguish normal and abnormal pS129, b) help us better understand the process leading to the pathology, c) further our understanding and refine pS129 as a biomarker for diseases of LBD and related synucleinopathies including PD, and eventually contribute to devising meaningful therapeutic interventions. An ideal full-time student: 1) is expected to design and perform experiments in a collaborative wet lab environment, and 2) will work with mice & rats, cultured rodent neurons, and postmortem human brain lysates.