The synucleinopathies are collection of disorders characterized by accumulation of aggregated ?-synuclein and include dementia with Lewy bodies (DLB), Parkinson's disease (PD), Parkinson's disease with dementia (PDD), and multisystem atrophy (MSA). These synucleinopathies show different distributions of ?-synuclein pathology but all show pathology in the substantia nigra dopamine neurons. Together, DLB and PDD are estimated to make up ~25% of all degenerative dementias worldwide. Based on post-mortem brain studies, Heiko Braak and colleagues hypothesized that ?-synuclein pathology spreads from cell to cell in a retrograde (dendrite to axon) pattern from the brain stem anteriorly. Subsequent studies have observed ?-synuclein aggregates in PDD and DLB gastrointestinal (GI) tract. Coupled with observations that vagotomy is significantly protective against PD suggests that the origin of ?-synuclein spreading pathology may be in the GI tract. We have modeled this process using injection of ?-synuclein pre-formed fibrils (PFFs) into the pylorus and duodenum of mice. We observe a spread of ?-synuclein pathology in a pattern reminiscent of that described by Braak. Using this model, we propose a series of studies to identify neural circuits that accumulate ?-synuclein aggregates in GI-inject PFF mice and determine how this accumulation affect the synaptic function and connectivity within the circuit. In this application, we propose to (1) molecularly and anatomically identify input neurons to subtantia nigra dopamine neuron using recombinant rabies virus based RNAseq method, (2) determine the timecourse and extent of toxic ?-synuclein spread in these input neurons, and (3) determine the consequence of ?-synuclein spread on the function and connectivity of neurons innervating the nigral dopamine neurons. At the completion of these experiments, we will have improved our understanding how ?-synuclein disrupts neural circuits involved in cognitive processes, the underlying cause of dementia in DLB and PDD.
The spread of toxic ?-synuclein protein aggregates through the brain causes dementia with Lewy bodies and Parkinson's disease with dementia, together representing the second most common form of neurodegenerative dementia. Using a model that recapitulates spread of ?-synuclein pathology in the mouse, we propose a series of experiment to dissect the how toxic ?-synuclein affects normal neural circuit function giving insight into the disease process that leads to dementia.
