A neuropathological hallmark of a group of neurodegenerative diseases, known as human 'synucleinopathies', is the presence of intracellular protein aggregates, Lewy bodies (LB), upon postmortem brain examination. The alpha-synuclein protein is a major component of LB. Parkinson's disease (PD) is the prototype of human 'synucleinopathies'and has been studied extensively. Genome-wide association studies (GWAS) have implicated the alpha-synuclein (SNCA) gene as a central player in the pathogenesis of PD. Several studies in cell-cultures and animal models reported that over expression of wild-type SNCA can be toxic and may lead to cell death. Moreover, previously we documented elevated SNCA expression in sporadic-PD patients. Describing the molecular mechanisms underlying the regulation of SNCA expression, and any genetic variability that impinges on this regulation, is highly important for understanding the pathogenesis of LB related diseases. The overarching goal of this proposal is to understand the genetic elements controlling SNCA expression. We will further investigate whether any genetic variants in SNCA locus and/or changes in gene expression are associated with a broad-spectrum of LB diseases, focusing on autopsy-confirmed cases of dementia with Lewy bodies (DLB) and LB presentation in Alzheimer's disease (AD). To accomplish our goals, we will address the following specific aims: 1. Determine whether SNCA variants are associated with LB neuropathology in neurodegenerative diseases, specifically in AD and DLB. 2. Determine whether genetic variability in the SNCA locus alters SNCA-mRNA and protein expression in different anatomic areas of neuropathologically normal and LB-affected human brains;3. Explore in depth candidate sub-regions within the SNCA locus to identify novel variants that contribute to the risk to develop LB pathology, and evaluate their effect on SNCA expression. The fulfillment of these aims will enrich our understanding of the genetic basis of variability in SNCA expression and the general relevance of these variants to LB pathology. Moreover, the proposed studies will enhance our understanding of the genetic risk factors and molecular mechanisms that contribute to LB diseases including PD and provide valuable information for developing therapies targeting SNCA expression levels.

Public Health Relevance

Human 'synucleinopathies'including Parkinson's disease (PD), are common neurodegenerative diseases worldwide and poses an enormous health burden on the society. Currently, there is no method to prevent these diseases or to slow their progression. This group of diseases is characterized by neuropathology of Lewy bodies that consist of alpha-synuclein aggregates. Alpha-synuclein (SNCA) is implicated in the genetics and pathogenesis of PD. The proposed project aims to investigate the genetic basis underlying the regulation of SNCA expression in relation to susceptibility to the spectrum of Lewy body neuropathologies. The results will provide a better understanding of the genetic factors and molecular mechanisms underlying 'synucleinopathies'and will advance the identification of valuable pathways for developing therapies targeting SNCA expression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS085011-02
Application #
8739685
Study Section
Molecular Neurogenetics Study Section (MNG)
Program Officer
Sutherland, Margaret L
Project Start
2013-09-25
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
Afek, A; Tagliafierro, L; Glenn, O C et al. (2018) Toward deciphering the mechanistic role of variations in the Rep1 repeat site in the transcription regulation of SNCA gene. Neurogenetics 19:135-144
Kantor, Boris; Tagliafierro, Lidia; Gu, Jeffrey et al. (2018) Downregulation of SNCA Expression by Targeted Editing of DNA Methylation: A Potential Strategy for Precision Therapy in PD. Mol Ther 26:2638-2649
Tagliafierro, Lidia; Glenn, Omolara-Chinue; Zamora, Madison E et al. (2017) Genetic analysis of ?-synuclein 3' untranslated region and its corresponding microRNAs in relation to Parkinson's disease compared to dementia with Lewy bodies. Alzheimers Dement 13:1237-1250
Chiba-Falek, Ornit (2017) Structural variants in SNCA gene and the implication to synucleinopathies. Curr Opin Genet Dev 44:110-116
Tagliafierro, Lidia; Bonawitz, Kirsten; Glenn, Omolara C et al. (2016) Gene Expression Analysis of Neurons and Astrocytes Isolated by Laser Capture Microdissection from Frozen Human Brain Tissues. Front Mol Neurosci 9:72
Saul, Robert; Lutz, Michael W; Burns, Daniel K et al. (2016) The SSV Evaluation System: A Tool to Prioritize Short Structural Variants for Studies of Possible Regulatory and Causal Variants. Hum Mutat 37:877-83
Tagliafierro, L; Chiba-Falek, O (2016) Up-regulation of SNCA gene expression: implications to synucleinopathies. Neurogenetics 17:145-57
Lutz, Michael W; Saul, Robert; Linnertz, Colton et al. (2015) A cytosine-thymine (CT)-rich haplotype in intron 4 of SNCA confers risk for Lewy body pathology in Alzheimer's disease and affects SNCA expression. Alzheimers Dement 11:1133-43
Gottschalk, William K; Lutz, Michael W; He, Yu Ting et al. (2014) The Broad Impact of TOM40 on Neurodegenerative Diseases in Aging. J Parkinsons Dis Alzheimers Dis 1:
Linnertz, Colton; Lutz, Michael W; Ervin, John F et al. (2014) The genetic contributions of SNCA and LRRK2 genes to Lewy Body pathology in Alzheimer's disease. Hum Mol Genet 23:4814-21