The accumulation of misfolded proteins represents a common pathological mechanism of most major neurodegenerative disorders. Neuronal inclusions comprised of aggregated ?-Synuclein (aSyn), known as Lewy bodies (LBs) and Lewy-neurites (LNs), represent a key histopathological feature of Parkinson's disease (PD) and a family of related disorders known as synucleinopathies, most notably Dementia with LBs (DLB). LBs are also a prominent feature in nearly half of Alzheimer's disease subjects. Mutations and amplifications in the SNCA gene encoding aSyn also cause familial forms of PD. Although a large body of histological and genetic evidence firmly indicate a correlation between aSyn accumulation and disease, it remains unclear how aSyn pathology actually forms and subsequently contributes to disease. We and others recently demonstrated that minute quantities of recombinant or patient-derived aSyn aggregates can catalyze the formation of toxic LBs/LNs in cultured neurons and healthy non-transgenic mice. In both human PD and animal models, this ?seeded? aSyn pathology progressively propagates and spreads to neuroanatomically connected regions, reminiscent of prion diseases. Importantly, animals with LBs/LNs recapitulate the cardinal features of PD, including progressive loss of dopamine-producing neurons and locomotor deficits. This R01 renewal addresses several key biological questions posed by our earlier findings and combines novel molecular, in vivo, and computational tools to further understand how LBs/LNs form, propagate, and ultimately contribute to neurodegeneration and neurological symptoms.
Aim 1 will identify at the neuron subtypes that develop LBs/LNs following inoculation with misfolded aSyn. By combining traditional histological methods with FACS-assisted single-neuron RNAseq, we will determine the molecular signatures associated with subpopulations that are vulnerable or resistant to LBs/LNs formation.
Aim 2 will examine how PD genetic risk factors reported in the literature intersect with aSyn pathobiology, by testing the effect of knock-down or knock- in of individual genes on the formation of seeded pathology and neuronal survival. Candidates that significantly alter either will be confirmed in vivo using knock-out/knock-in mouse lines. Lastly, Aim 3 will integrate our molecular, genetic, and in vivo experimental data together with publicly available connectivity and gene- expression atlases to interrogate the mechanisms of pathological spread. Using recently developed mathematical approaches to describe infectious agent spread, we will develop in silico models to understand aSyn pathology formation and spread. Completion of these studies should provide valuable insights into the potential mechanisms by which aSyn contribute to the progression of PD and related disorders. Increased understanding of the pathogenesis of this and related synucleinopathies should ultimately result in earlier detection and disease-modifying therapies for these currently incurable disorders.

Public Health Relevance

The brains of individuals with Parkinson's disease, dementia with Lewy bodies, and a significant portion of those with Alzheimer's disease gradually develop abnormal protein deposits called Lewy bodies, but it is not known how they form and contribute to disease. This study uses a recently discovered method that causes brain cells to form these lesions, allowing us to investigate which neurons in the brain are most affected by this disease process and how this type of pathology impairs the survival of these neurons. Better understanding of these processes would lead to a better understanding of disease progression and accelerate the development of new therapies for a host of neurodegenerative disorders such as Parkinson's, dementia with Lewy bodies, and Alzheimer's disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
2R01NS088322-06A1
Application #
10122276
Study Section
Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
Program Officer
Sieber, Beth-Anne
Project Start
2015-03-13
Project End
2025-11-30
Budget Start
2021-02-15
Budget End
2021-11-30
Support Year
6
Fiscal Year
2021
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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