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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS073740-03
Application #
8338803
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sutherland, Margaret L
Project Start
2011-09-30
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$342,344
Indirect Cost
$123,594
Name
Mayo Clinic Jacksonville
Department
Type
DUNS #
153223151
City
Jacksonville
State
FL
Country
United States
Zip Code
32224
Delenclos, Marion; Jones, Daryl R; McLean, Pamela J et al. (2016) Biomarkers in Parkinson's disease: Advances and strategies. Parkinsonism Relat Disord 22 Suppl 1:S106-10
Helferich, Anika M; McLean, Pamela J; Weishaupt, Jochen H et al. (2016) Commentary: alpha-synuclein interacts with SOD1 and promotes its oligomerization. J Neurol Neuromedicine 1:28-30
Jiang, Peizhou; Gan, Ming; Yen, Shu-Hui et al. (2016) Proaggregant nuclear factor(s) trigger rapid formation of α-synuclein aggregates in apoptotic neurons. Acta Neuropathol 132:77-91
Levin, Johannes; Hillmer, Andreas S; Högen, Tobias et al. (2016) Intracellular formation of α-synuclein oligomers and the effect of heat shock protein 70 characterized by confocal single particle spectroscopy. Biochem Biophys Res Commun 477:76-82
Delenclos, Marion; Trendafilova, Teodora; Jones, Daryl R et al. (2015) A Rapid, Semi-Quantitative Assay to Screen for Modulators of Alpha-Synuclein Oligomerization Ex vivo. Front Neurosci 9:511
Moussaud, Simon; Malany, Siobhan; Mehta, Alka et al. (2015) Targeting α-synuclein oligomers by protein-fragment complementation for drug discovery in synucleinopathies. Expert Opin Ther Targets 19:589-603
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
Yue, M; Hinkle, K M; Davies, P et al. (2015) Progressive dopaminergic alterations and mitochondrial abnormalities in LRRK2 G2019S knock-in mice. Neurobiol Dis 78:172-95
Delenclos, Marion; Moussaud, Simon; McLean, Pamela J (2015) Untangling a role for tau in synucleinopathies. Biol Psychiatry 78:666-7
Eschbach, Judith; von Einem, Björn; Müller, Kathrin et al. (2015) Mutual exacerbation of peroxisome proliferator-activated receptor γ coactivator 1α deregulation and α-synuclein oligomerization. Ann Neurol 77:15-32

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