Friday, November 22, 2024
11/22/2024
ABSTRACT/SUMMARY Synucleinopathies, including Parkinson’s disease (PD) and Dementia with Lewy Bodies (DLB), are neurodegenerative diseases characterized by the abnormal aggregation of α-synuclein. Furthermore, it is well known that α-synuclein exists in multiple structural forms (i.e., monomers and oligomers) that contribute to neurotoxicity by distinct mechanisms. While there is substantial evidence that accumulation of α-synuclein broadly impairs synaptic vesicle endocytosis, the effects of distinct α-synuclein species on synaptic endosomal trafficking are largely unknown. The proposed studies will be the first to investigate in detail how accumulation of different oligomeric α-synuclein species affect endosomal trafficking at vertebrate synapses and the underlying cellular and molecular mechanisms. Using the lamprey synapse model, a classical vertebrate model, we can deliver precise amounts of purified -synuclein species directly into synapses. This allows us to independently test the effects of different -synuclein species on presynaptic ultrastructure and function. Our preliminary studies suggest that excess monomeric -synuclein impairs endosomal trafficking, as shown by a reduction in the number of synaptic vesicles and concomitant increase in the number of atypical large vesicles, reminiscent of endosomes. This provides an excellent model for the proposed studies. In Aim 1 (K99), we will determine how monomeric human -synuclein affects endosomal trafficking at synapses. In Aim 2 (R00), we will determine how oligomeric human -synuclein contribute to -synuclein-mediated endosomal dysfunction at synapses. The focus will be on different oligomeric -synuclein species including dimers, small oligomers and larger oligomers from PD/DLB human brains. These studies will provide critical understanding for the development of therapies for improving synaptic function in synucleinopathies.
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