Synaptic vesicle changes in synucleinopathies

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The central objective of this proposal is to quantify changes in synaptic vesicle (SV) pools and composition over aging and in Alzheimer's Disease Related Dementias such as Lewy body dementia and Parkinson’s dis-ease. SVs mediate neurotransmitter release at the synapse. Their abundance and uniform size have enabled extensive biochemical studies, and ~15% of SV proteins have been linked to CNS diseases, with numerous of them in Alzheimer's Disease Related Dementias and Parkinson’s disease. Yet, no study has analyzed SV sub-types, defined by their vesicular neurotransmitter transporter, or changes in SV composition or pools with aging and in Parkinson’s disease and Alzheimer's Disease Related Dementias such as Lewy body dementia. Most SV proteins are low abundant, with a copy number of <1 per SV. This suggests molecular and functional SV diversity, necessitating a thorough and mechanistic analysis of SV pools and composition. α-Synuclein (αSyn) exists in a SV-bound and a cytosolic state, exchanging between these pools in a dynamic equilibrium. SV-bound αSyn mediates its physiological functions at the synapse. Aggregation of αSyn is a pathological hallmark of Parkinson’s disease, Lewy body dementia and other Alzheimer's Disease Related Dementias, and a large fraction of αSyn aggregates occurs in presynaptic boutons. Pathology has been suggested to be associated with altered αSyn:lipid interactions, and several SV proteins are linked to Parkinson’s disease, Lewy body dementia and other Alzheimer's Disease Related Dementias. Thus, changes in SV lipids or proteins could alter binding of αSyn to SVs. The hypothesis is that reduced SV-binding of αSyn is a precipitating factor for αSyn-linked pathology, and that changes in SV numbers, protein and/or lipid composition account for the reduction in αSyn binding. Guided by our strong preliminary data, revealing reduced SV-binding of αSyn in two Parkinson’s disease mouse models and in brain tissue of Parkinson’s disease and Lewy body dementia patients in addition to an age-dependent reduction of SV density in our humanized αSyn mouse model, this hypothesis will be tested in two specific aims: 1) Determine changes in synaptic vesicle numbers and pools, and 2) Determine changes in SV composition. The study is expected to provide a systematic understanding of the changes in SV pools and composition during aging and in Parkinson’s disease, Lewy body dementia and other Alzheimer's Disease Related Dementias, which lays the foundation to dive further into mechanistic studies. This work is innovative because it will generate high-resolution maps of SVs of different neurotransmitter subtypes over the course of aging and αSyn-linked pathology. The work is significant because it (1) determines for the first time changes in SV composition during aging, (2) determines for the first time the composition of SV subtypes, (3) has important implications for Parkinson’s disease, Lewy body dementia and other Alzheimer's Disease Related Dementias, (4) may provide clues towards cell-type specific vulnerability in Alzheimer's Disease Related Dementias such as Lewy body dementia and in Parkinson’s disease.