Characterization of a novel VAMP2 pathology in Parkinson's disease

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  • Thesis download: available for open access on 17 Nov 2018.

Gao, JianQun, 2015 Characterization of a novel VAMP2 pathology in Parkinson's disease, Flinders University, School of Medicine

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Abstract

In addition to its well-established contribution to classical clinical manifestation, emerging evidence suggests synaptic degeneration may be an early event in neurodegeneration in Parkinson’s disease (PD). VAMP2 (Synaptobrevin-2) is the synaptic vesicle protein that forms the SNARE complex, the protein machinery for neurotransmitter release, with the presynaptic plasma membrane-resided proteins syntax-1 and SNAP-25. The maintenance of sufficient number and functional conformation of VAMP2 on synaptic vesicles is tightly regulated for proper neurotransmitter release, and its dysfunction may contribute to neurological diseases. By using immunohistochemistry and immunoblot, we identified the N-terminally truncated VAMP2 (tVAMP2), but not the full-length VAMP2 (fVAMP2), as an important component of Lewy bodies isolated from brains of PD and DLB (Dementia with Lewy bodies), and tVAMP2 positive-stained Lewy bodies (LBs) and Lewy neurites (LNs) were detected in various regions of PD brain. This robust immunoreactivity of tVAMP2 in Lewy pathologies was comparable to that of α-synuclein, the prominent component of Lewy bodies and Lewy neurites, both of which were pathological characteristics of PD and DLB. Furthermore, using immunofluorescence double-staining, we showed co-localization of tVAMP2 and α-synuclein in Lewy bodies and Lewy neurites, suggesting their synergetic effect on the formation of Lewy bodies and Lewy neurites. Finally, in purified Lewy bodies from PD and DLB brains, the presence of two human VAMP2 fragments (aa32-47 and aa60-83) was confirmed by mass spectrometry, while a large peptide at the N-terminus (aa2-30) was undetectable. These findings indicated the unique value of tVAMP2 in understanding the pathogenesis and pathological diagnosis of PD and DLB. Further experiments are required to identify the N-terminal truncation site.

Keywords: VAMP2, Parkinson's disease
Subject: Medicine thesis

Thesis type: Masters
Completed: 2015
School: School of Medicine
Supervisor: Dr Timothy Chataway