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.
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.
|Jiang, Peizhou; Gan, Ming; Yen, Shu-Hui et al. (2017) Histones facilitate ?-synuclein aggregation during neuronal apoptosis. Acta Neuropathol 133:547-558|
|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|
|Levin, Johannes; Hillmer, Andreas S; Högen, Tobias et al. (2016) Intracellular formation of ?-synuclein oligomers and the effect of heat shock protein 70 characterized by confocal single particle spectroscopy. Biochem Biophys Res Commun 477:76-82|
|Jarvela, Timothy S; Lam, Hoa A; Helwig, Michael et al. (2016) The neural chaperone proSAAS blocks ?-synuclein fibrillation and neurotoxicity. Proc Natl Acad Sci U S A 113:E4708-15|
|Jiang, Peizhou; Gan, Ming; Yen, Shu-Hui et al. (2016) Proaggregant nuclear factor(s) trigger rapid formation of ?-synuclein aggregates in apoptotic neurons. Acta Neuropathol 132:77-91|
|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|
|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|
|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|
|Lindberg, Iris; Shorter, James; Wiseman, R Luke et al. (2015) Chaperones in Neurodegeneration. J Neurosci 35:13853-9|
|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|
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