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.
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.
|Brennan, Laura; Siderowf, Andrew; Rubright, Jonathan D et al. (2016) The Penn Parkinson's Daily Activities Questionnaire-15: Psychometric properties of a brief assessment of cognitive instrumental activities of daily living in Parkinson's disease. Parkinsonism Relat Disord 25:21-6|
|Fullard, Michelle E; Tran, Baochan; Xie, Sharon X et al. (2016) Olfactory impairment predicts cognitive decline in early Parkinson's disease. Parkinsonism Relat Disord 25:45-51|
|Roalf, David R; Moore, Tyler M; Wolk, David A et al. (2016) Defining and validating a short form Montreal Cognitive Assessment (s-MoCA) for use in neurodegenerative disease. J Neurol Neurosurg Psychiatry :|
|Brettschneider, J; Irwin, D J; Boluda, S et al. (2016) Progression of alpha-synuclein pathology in multiple system atrophy of the cerebellar type. Neuropathol Appl Neurobiol :|
|Biundo, Roberta; Weis, L; Bostantjopoulou, S et al. (2016) MMSE and MoCA in Parkinson's disease and dementia with Lewy bodies: a multicenter 1-year follow-up study. J Neural Transm (Vienna) 123:431-8|
|Lim, Nicholas S; Swanson, Christine R; Cherng, Hua-Ren et al. (2016) Plasma EGF and cognitive decline in Parkinson's disease and Alzheimer's disease. Ann Clin Transl Neurol 3:346-55|
|Price, Amy Rose; Peelle, Jonathan E; Bonner, Michael F et al. (2016) Causal Evidence for a Mechanism of Semantic Integration in the Angular Gyrus as Revealed by High-Definition Transcranial Direct Current Stimulation. J Neurosci 36:3829-38|
|Chahine, Lama M; Weintraub, Daniel; Hawkins, Keith A et al. (2016) Cognition in individuals at risk for Parkinson's: Parkinson associated risk syndrome (PARS) study findings. Mov Disord 31:86-94|
|Tuttle, Marcus D; Comellas, Gemma; Nieuwkoop, Andrew J et al. (2016) Solid-state NMR structure of a pathogenic fibril of full-length human Î±-synuclein. Nat Struct Mol Biol 23:409-15|
|White, Matthew T; Shaw, Leslie M; Xie, Sharon X et al. (2016) Evaluation of Cerebrospinal Fluid Assay Variability in Alzheimer's Disease. J Alzheimers Dis 51:463-70|
Showing the most recent 10 out of 250 publications