Alpha‐synuclein (SNCA) genetic variability has been implicated in many susceptibility studies of idiopathic PD and to a lesser extent in MSA and DLB/DLBD, although the precise mechanisms underlying these associations remain elusive. SNCA association studies are largely based on motor phenotypes, limited SNCA genotyping (Rep1 or specific SNPs) and cross‐sectional studies. Only few investigators have looked at SNCA variability in terms of disease progression or cognitive outcomes. Nevertheless, the majority of patients with PD will suffer mild cognitive impairment (PD‐MCI) and possibly dementia in advanced disease (PDD) reminiscent of SNCA multiplication duplication and triplication carriers. Both cognitive and motor functions are evolutionarily related to the physiologic role of alpha‐synuclein in synaptic plasticity (with age/disease‐associated compensation) and conversely to the protein’s pathologic role in the development of Lewy body disease.
We hypothesize PD‐MCI may be a more reliable marker of early disease progression, and of disease‐modification/neuroprotection than motor dysfunction, given measurement of motor symptoms may be confounded by medication.
Aims & Expected Results
SNCA genetic variability highlights a relationship between PD, PD‐MCI, PDD and perhaps DLB, nominating its use as a biomarker. However, further correlative analyses of SNCA genetic variability with disease progression, especially in terms of cognitive decline, gene/protein expression and Lewy pathology are required.
We are currently using targeted DNA custom capture and next-generation sequencing to comprehensively characterize the entire 135kb SNCA genomic locus in worldwide populations. We will then assess the contribution of SNCA genetic variability to the gene/protein expression levels, and to the ultimate distribution/burden of Lewy pathology in a brain autopsy series of PD. Finally, association of SNCA genetic variability with longitudinal data on PD‐MCI and PDD will be tested, in order to identify and refine its contribution to the trajectory of cognitive decline and dementia in PD.
The findings will extend prior association studies and are likely to provide a greater mechanistic understanding for targeted therapeutics already in development. SNCA genetic variability may inform physicians and patients with PD of the risk of cognitive dysfunction and of the trajectory of that decline. SNCA genetic variability may be employed to optimize stratification in clinical trials of PD, similar to apoE4 genotyping in Alzheimer`s disease.