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Funded Studies

Alpha-synuclein and Cognitive Decline in Parkinson’s Disease

Objective/Rationale:             
Variability in the SNCA gene (which encodes alpha-synuclein, the protein that clumps in Parkinson’s disease) is a major risk factor for PD. Using next-generation sequencing we will characterize SNCA and see whether genetic variability is associated with the trajectory of motor and cognitive decline in patients. In post-mortem patient brains we will also evaluate the genetic contribution of SNCA to gene expression and alpha-synuclein clumping. This project is a collaboration between geneticists at the University of British Columbia, the Movement Disorders Society PD-MCI Consortium (23 international sites) and the Parkinson’s UK Brain Bank.

Project Description:
We will perform next-generation sequencing of SNCA for 800 patients (~400 deceased), with genotyping in several thousand more patients to follow up. We plan to test whether SNCA genetic variability is associated with: i) motor, cognitive and neuropsychiatric disturbances; ii) conversion from PD without cognitive disturbances to PD with mild cognitive impairment or with dementia, as well as; iii) the slope of decline. From post-mortem brain tissue will also include a study of SNCA genetic variability, alpha-synuclein gene and protein expression in brain tissue.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:                     
In PD, while many individuals are cognitively preserved into later life, a subset develop mild cognitive impairment and subsequent dementia. This study may provide a genetic biomarker that could help predict and distinguish between these trajectories/outcomes.

Anticipated Outcome:          
The results will extend prior SNCA association studies of motor dysfunction, may inform physicians and patients with PD of the risk of cognitive dysfunction and the path of decline, and are likely to provide a better mechanistic understanding for targeted therapeutics already in development.

Progress Report

Alpha-synuclein (SNCA) genetic variability has been implicated in many susceptibility studies of idiopathic Parkinson’s disease (PD), Dementia with Lewy bodies (DLB, typically described as Diffuse Lewy body Disease (DLBD) post-mortem) and to a lesser extent multiple system atrophy (MSA). However, which precise variant within the region contributes to the clinical (movement and cognitive) or pathologic phenotypes is unclear. In this study we proposed to sequence the entire SNCA genomic locus (and171 other genes implicated in dopamine metabolism, parkinsonism, dementia and neurodegeneration) to identify specific SNCA biomarkers. Towards this end complete resequencing and/or genotyping has been accomplished for: a) de novo PD (the entire Parkinson’s Progressive Markers Initiative series); b) four PD-MCI cohorts (patients with >5 progression with detailed longitudinal evaluation beyond another 3-8 years and data on PD‐MCI and PDD to MCI (level II) criteria), and; c) autopsy-confirmed Lewy body disease, including patients diagnosed with PD, PDD and DLB (Parkinson’s UK brain bank, Oxford University and Mayo Foundation).

Preliminary analysis has leverage pre‐existing data on cognitive and motor impairment, to deduce which regions of the SNCA locus and which specific variants drive association to PD without cognitive impairment, PD with dementia (PDD), and DLB. In the brain autopsy series we have begun to systematically quantify alpha‐synuclein immunoreactivity by genotype/haplotype, and to correlate alpha‐synuclein genetic variability, gene and protein expression. We have also been actively seeking additional data and samples for a validation series, both within and beyond the PD-MCI Consortium, as originally proposed.


Researchers

  • Lefkos T. Middleton, MD, FRCP

    London United Kingdom


  • Matthew Farrer, PhD

    Vancouver Canada


  • Gert J. Geurtsen, PhD, MSc

    Amsterdam Netherlands


  • Irene Litvan, MD

    La Jolla, CA United States


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