The goal of this application is to investigate the impact of extracellular alpha-synuclein on neurodegeneration and disease progression in Parkinson's disease (PD). There are several reasons to target extracellular alpha-synuclein for the development of novel therapeutic agents for PD including the fact that Lewy bodies containing alpha-synuclein have been found in healthy grafted neurons in PD patients several years after transplant suggesting a possible role for alpha-synuclein transmission in disease propagation and progression. We have proposed complementary approaches to elucidate not only the fundamental mechanisms and species involved in alpha-synuclein release, but to develop unique therapeutic interventions that target extracellular alpha- synuclein oligomers with a view that understanding extracellular alpha-synuclein biology can lead to a translation of new or different therapeutic approaches. We will examine 3 major aims:
The first aim will define the types of alpha-synuclein released from neurons using a series of biophysical and molecular tools that allow characterization of released oligomeric forms of alpha-synuclein. We will also investigate the mechanisms involved in the release and uptake of alpha-synuclein and the impact of extracellular alpha-synuclein on cell viability .
The second aim will expand on our preliminary studies and on recently published studies to investigate pathways involved in alpha-synuclein release and uptake and in particular the role of macroautophagy in alpha-synuclein release and uptake. Finally, the third aim extends these observations in vivo, utilizing in vivo microdialysis and AAV introduced forms of alpha-synuclein that are neurotoxic in vitro, and furthermore extends the hypothesis that macroautophagy can modulate alpha-synuclein release and uptake in vivo. Together, we will be able to determine which species of alpha-synuclein are released from cells and ultimately taken up by neighboring cells;the mechanisms associated with release and uptake;and if manipulations affecting alpha-synuclein release and uptake affect alpha-synuclein-induced toxicity in cells and animal models with the goal of translation into the clinic.

Public Health Relevance

The goal of this proposal is to investigate the impact of extracellular alpha-synuclein on neurodegeneration and disease progression in Parkinson's disease. Understanding extracellular alpha-synuclein biology may lead to the translation of new or different therapeutic approaches to halt or reverse disease progression in PD.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Sutherland, Margaret L
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Mayo Clinic Jacksonville
United States
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Gan, Ming; Moussaud, Simon; Jiang, Peizhou et al. (2015) Extracellular ATP induces intracellular alpha-synuclein accumulation via P2X1 receptor-mediated lysosomal dysfunction. Neurobiol Aging 36:1209-20
Eschbach, Judith; von Einem, Björn; Müller, Kathrin et al. (2015) Mutual exacerbation of peroxisome proliferator-activated receptor ? coactivator 1? deregulation and ?-synuclein oligomerization. Ann Neurol 77:15-32
Winslow, Ashley R; Moussaud, Simon; Zhu, Liya et al. (2014) Convergence of pathology in dementia with Lewy bodies and Alzheimer's disease: a role for the novel interaction of alpha-synuclein and presenilin 1 in disease. Brain 137:1958-70
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