Inclusions comprised of alpha-synuclein (a-syn), i.e. Lewy bodies (LBs) and Lewy neurites (LNs), define Parkinson's disease (PD), PD with dementia (PDD), and dementia with Lewy Bodies (DLB). DLB manifests with neuropathology typical of Alzheimer's disease (AD) in addition to LBs/LNs and given that LBs/LNs are present in ~50% of AD brains, PD, PDD, DLB, and AD may represent overlapping neurodegenerative disorders. However, the precise relationship between the clinical phenotypes and each class of central nervous system (CNS) lesions as well as their pathogenic mechanisms are poorly understood. We hypothesize that the progression of DLB and that of PD to PDD result from selective vulnerability of neurons in different brain regions and the cell-to-cell "transmission" of distinct pathological a-syn species (strains) that differentially promote a-syn and AD pathology in a disease- and brain region-specific manner. To test this hypothesis, we developed a unique neuron-based model of LBs/ LNs to study concomitant a-syn and AD pathology. Briefly, the application of synthetic human a-syn pre-formed fibrils (PFFs) to primary neurons from non-transgenic (non-Tg) mice seeds recruitment and conversion of soluble endogenous mouse a-syn into insoluble LB/LN-like inclusions with deleterious biological and functional consequences. Notably, endogenous mouse tau also is recruited into insoluble tau aggregates in a strain-dependent manner. This model opens up exciting new opportunities for elucidating mechanisms underlying the transmission of pathological a-syn and the role of various a-syn strains in the induction of a-syn and AD pathology during the progression of PD, PDD and DLB. Biochemical, biophysical and cell biological approaches will be used to determine if and how individual synthetic a-syn strains differ in their capacity to recruit endogenous a-syn into LBs/LNs and promote AD-like tau pathology. We will also verify the presence of a-syn strains in authentic LB/LN enriched preparations generated from PD, PDD and DLB brains characterized genetically and neuropathologically through Core C from patients followed by Core B and studied in Projects 1 and II to determine selective vulnerability and a-syn strains. Thus the Aims of Project IV are to: 1) Test the hypothesis that neurons from different CNS regions are selectively vulnerable to develop either LBs/LNs alone or LBs/LNs with AD-like tau pathology and altered levels of secreted Abeta In response to treatment with distinct a-syn PFF strains;2) Generate and characterize synthetic a-syn PFFs strains that differentially modulate the LBs/LNs and AD pathology;3) Determine if enriched LBs/LNs fractions isolated from different regions of PD/PDD/DLB brains, will differentially "seed" and "cross-seed" the recruitment of endogenous a-syn and tau into insoluble aggregates in primary neurons, thus reflecting strain-like properties;4) Collaborate with Project IV to identify anti-a-syn monoclonal antibodies that block a-syn transmission in neuron-based synucleinopathy models to be used for immunotherapy in a-syn Tg mice of Project IV.

Public Health Relevance

The proposed Studies will lead to a better understanding of mechanisms of a-syn mediated neurodegeneration and disease progression in PD/PDD/DLB and provide novel insights into targets for developing potential therapies for these and related synucleinopathies. Specifically, Project III will have significant translational impact on efforts to develop biomarkers and novel immune therapies for PD/PDD/DLB and related a-synucleinopathies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Specialized Center (P50)
Project #
5P50NS053488-08
Application #
8705042
Study Section
Special Emphasis Panel (ZNS1-SRB-J)
Project Start
Project End
Budget Start
2014-07-01
Budget End
2015-06-30
Support Year
8
Fiscal Year
2014
Total Cost
$274,731
Indirect Cost
$103,030
Name
University of Pennsylvania
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kalia, Lorraine V; Lang, Anthony E; Hazrati, Lili-Naz et al. (2015) Clinical correlations with Lewy body pathology in LRRK2-related Parkinson disease. JAMA Neurol 72:100-5
Swanson, Christine R; Li, Katherine; Unger, Travis L et al. (2015) Lower plasma apolipoprotein A1 levels are found in Parkinson's disease and associate with apolipoprotein A1 genotype. Mov Disord 30:805-12
Irwin, David J; McMillan, Corey T; Suh, EunRan et al. (2014) Myelin oligodendrocyte basic protein and prognosis in behavioral-variant frontotemporal dementia. Neurology 83:502-9
Luk, Kelvin C; Lee, Virginia M-Y (2014) Modeling Lewy pathology propagation in Parkinson's disease. Parkinsonism Relat Disord 20 Suppl 1:S85-7
Avants, Brian B; Libon, David J; Rascovsky, Katya et al. (2014) Sparse canonical correlation analysis relates network-level atrophy to multivariate cognitive measures in a neurodegenerative population. Neuroimage 84:698-711
Peelle, Jonathan E; Powers, John; Cook, Philip A et al. (2014) Frontotemporal neural systems supporting semantic processing in Alzheimer's disease. Cogn Affect Behav Neurosci 14:37-48
Cook, Philip A; McMillan, Corey T; Avants, Brian B et al. (2014) Relating brain anatomy and cognitive ability using a multivariate multimodal framework. Neuroimage 99:477-86
Ash, Sharon; Menaged, Anna; Olm, Christopher et al. (2014) Narrative discourse deficits in amyotrophic lateral sclerosis. Neurology 83:520-8
McCluskey, Leo; Vandriel, Shannon; Elman, Lauren et al. (2014) ALS-Plus syndrome: non-pyramidal features in a large ALS cohort. J Neurol Sci 345:118-24
Escobar, Valerie Drews; Kuo, Yien-Ming; Orrison, Bonnie M et al. (2014) Transgenic mice expressing S129 phosphorylation mutations in ?-synuclein. Neurosci Lett 563:96-100

Showing the most recent 10 out of 105 publications