The personal and societal costs of Parkinson's disease (PD) are expected to increase significantly in the next two decades. The mechanisms of neurodegeneration are not well understood, and no treatment clearly slows the neurodegenerative process in PD. Alpha-synuclein (?syn) is a protein that is central to PD pathogenesis, and recent studies show that the transmission of ?syn between different cell populations is key to its ability to cause toxicity. Release of ?syn is the first critical componen of transmission, and occurs through exosomal and non-exosomal mediated pathways. A second key feature of prion-like spread of ?syn is the uptake in target neurons, leading to consequent misfolding of endogenous ?syn. What mechanisms regulate the release and spread of ?syn pathology are not known. The 14-3-3 proteins are chaperone-like proteins that can reduce protein aggregation, regulate protein secretion, and promote cell survival. We have previously shown that 14-3-3s are protective in several models of PD and can regulate the exosomal release of LRRK2, a key protein implicated in PD. In this proposal, we present preliminary data that overexpression of the 14-3-3? isoform in ?syn-producing cells reduces the toxicity of released ?syn. Our central hypothesis is that 14-3-3 proteins can protect against ?syn toxicity by reducing the transmission of toxic ?syn species.
In Aims 1 and 2, we will investigate whether 14-3-3s can regulate ?syn release through exosomes or alternative non-exosomal pathways and assess how any changes in release impacts paracrine ?syn toxicity. For these studies, we will use a paracrine inducible ?syn culture system in which released ?syn induced cell death in separately culture primary neurons.
In Aim 1, we will use biochemical and imaging approaches to determine if 14-3-3s alter the amount and conformation of ?syn in exosomes. We will also assess how alterations in exosomal ?syn impact paracrine ?syn toxicity.
In Aim 2, we will use similar techniques to test if 14-3-3s reduce ?syn release and toxicity through inhibition of the recycling endosomal pathway.
In Aim 3, we will focus on the effects of 14-3-3s in target cells exposed to extracellular ?syn. Specifically, we will use in vitro and in vivo ?syn fibril models to test whether 14-3-3s can reduce ?syn uptake, aggregation, and toxicity in these models. If we can establish that 14-3-3s regulate the pathological transmission of ?syn, this would justify exploration of potential PD therapies targeting the 14-3-3s.

Public Health Relevance

Parkinson's disease (PD) is the second most common neurodegenerative disorder with no current therapies that slow disease progression. In this proposal, we will investigate the role of 14-3-3 proteins in the regulation of alpha-synuclein transmission, a key protein linked to PD with prion-like properties. Our long-term goal is to establish whether 14-3-3s may be a therapeutic target for this disabling disorder.

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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University of Alabama Birmingham
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Wang, Bing; Underwood, Rachel; Kamath, Anjali et al. (2018) 14-3-3 Proteins Reduce Cell-to-Cell Transfer and Propagation of Pathogenic ?-Synuclein. J Neurosci 38:8211-8232
Underwood, Rachel; Yacoubian, Talene A (2017) Disparate genes come together: Spatial and genetic screens point to disruptions in vesicle trafficking and mRNA metabolism in synucleinopathies. Mov Disord 32:840
McFerrin, Michael B; Chi, Xiaofei; Cutter, Gary et al. (2017) Dysregulation of 14-3-3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology. Ann Clin Transl Neurol 4:466-477
Lavalley, Nicholas J; Slone, Sunny R; Ding, Huiping et al. (2016) 14-3-3 Proteins regulate mutant LRRK2 kinase activity and neurite shortening. Hum Mol Genet 25:109-22
Ding, H; Underwood, R; Lavalley, N et al. (2015) 14-3-3 inhibition promotes dopaminergic neuron loss and 14-3-3? overexpression promotes recovery in the MPTP mouse model of Parkinson's disease. Neuroscience 307:73-82
Slone, Sunny Rae; Lavalley, Nicholas; McFerrin, Michael et al. (2015) Increased 14-3-3 phosphorylation observed in Parkinson's disease reduces neuroprotective potential of 14-3-3 proteins. Neurobiol Dis 79:1-13