Harnessing Neuroplasticity Genes to Combat Synucleinopathy-Mediated Axonopathy
Abstract
Parkinson’s disease (PD) is the second most common neurodegenerative disease. The pathological hallmark of the disease is accumulation of clumps of a protein called alpha-synuclein (a-syn) and thus the disease is classified as a “synucleinopathy.” A-syn is a protein normally found in the brain in a soluble form; for unknown reasons in the disease process, it is triggered to form clumps (aggregates) that are termed Lewy bodies. These Lewy bodies are found in neurons in the substantia nigra (and other regions), and multiple lines of evidence link a-syn aggregates to the degeneration of neurons in the nigrostriatal system, resulting in the classic motor impairment associated with PD. Further, there is evidence to support that nigrostriatal neurons first show dysfunction in their axons and synaptic connections with other neurons, prior to loss of the neurons themselves. The synapses that are the “business end” of the neuron are regulated by numerous genes collectively called “neuroplasticity genes”; these genes can determine how much neurotransmitter is released, how the synapse can communicate with the cell body, and with what other neurons the nigrostriatal neuron can communicate. Without a healthy synapse, a nigrostriatal neuron cannot function to control movement. Our ability to use animals to model the cascade of events in synucleinopathy depends on our ability to recapitulate all of the features of PD. My mentor has been one of a few scientists leading the characterization of a novel PD model of synucleinopathy. This model is called the a-syn preformed fibril (PFF model), and unlike previous animal models of PD, it allows us to study the relationship between the formation of endogenous a-syn aggregates and loss of nigrostriatal neurons. As with PD, the a-syn PFF model shows axonal changes prior to neurodegeneration. In this project, submitted in the “mechanisms of neuroplasticity in the PD brain” focus, I plan to leverage this model to directly examine what neuroplasticity genes are impacted in early synucleinopathy. With these results, I will continue studies on two top candidate neuroplasticity genes to determine whether manipulating expression levels can protect axons and cell bodies from synucleinopathy-induced degeneration. The end goal of my project is to promote neuroplasticity, the ability of the nigrostriatal synaptic terminal to function when faced with a synucleinopathy insult most relevant to the PD pathophysiology. The genetic signature that I will identify will provide multiple avenues for the development of genetic or pharmacological therapeutics to slow the progression of PD. My future research program can be built around further investigation of these synucleinopathy-induced neuroplasticity genes.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810233
Entities
People
- Joseph P Patterson
Organizations
- Michigan State University
- United States Army