Funded Studies
Objective/Rationale:
In addition to motor disorders, Parkinson disease (PD) patients also suffer from cognitive deficits, which are believed to result from abnormal accumulation of alpha-synuclein, a protein that is abundant in PD brains. Neurons are the basic structural and functional units of the brain, whereas dendritic spines are numerous tiny communication units between neurons. The objective of this proposal is to clarify the neurobiological basis of PD by examining how alpha-synuclein affects these tiny dendritic spines.
Project Description:
We will use our live imaging system to investigate how accumulation of alpha-synuclein proteins in neurons affects the structure of the dendritic spines. We will also poke a tiny glass pipette into cultured neurons and use an electronic device to record the electrical signals that the spines generate. The A53T genetic mutation in alpha-synuclein is known to be associated with familiar Parkinson’s disease. We will specifically look at how this mutation affects both the structure and function of dendritic spines. Another protein that is also known to play important roles in the pathogenesis of PD is the tau protein. We will use antibodies to monitor how the A53T mutation affects the location of tau proteins and will further determine the functional consequence of tau mislocalization.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
The proposed project will advance our understanding of PD pathogenesis by examining how the abnormal accumulation of alpha-synuclein and tau proteins affects the structure and function of dendritic spines, the basic communication units between neurons. The new information derived from the proposed study may provide novel drug targets for the prevention and treatment of PD.
Anticipated Outcome:
Both alpha-synuclein and tau proteins are known to play roles in PD pathogenesis. The proposed study will clarify the mechanistic link between these two proteins during the pathological development of PD.
Final Outcome
Dendritic spines are the fundamental functional units for many brain functions including learning and memory. PD patients frequently suffer from debilitating non-motor symptoms including cognitive decline, dementia and sleep disorders. The neurobiological mechanism underlying these non-motor symptoms remain unknown. We unraveled a novel cellular mechanism underlying morphological and functional deficits in dendritic spines caused by alpha-synuclein, a key player in Parkinson’s disease pathogenesis. The unraveled signaling pathway may provide new drug targets in future strategies for ameliorate these non-motor symptoms.