Parkinson disease (PD) is a neurodegenerative disease that was long considered the result of environmental factors. However, over the past 15 years, a genetic etiology for PD has begun to emerge. PD is now considered a multifactorial disorder that arises owing to a combination of genetic susceptibility and environmental factors. Although it is now clearly established that many, if not all, forms of PD have a genetic component, the majority of causal and disease-modifying variants remain unknown.
The ‘common disease-common variant’ hypothesis has been in vogue for some years. Despite numerous genome wide association studies and the identification of several trait associated variants, additional genetic factors remain to be identified.
We hypothesize that the latest sequencing technologies will expedite identification of novel genes with mutations for familial parkinsonism; findings that may generalize to idiopathic PD.
Aims & Expected Results
Many multi-incident families with highly penetrant parkinsonism, consistent with Mendelian inheritance
(autosomal dominant, recessive of X-linked disease transmission) have opted to take part in our research through worldwide clinical collaborations (in Canada, but also in Australia, Chile, France, Germany, India, Ireland, Israel, Korea, Norway, Faroes, South Africa, Sweden, Taiwan, Tunisia and the U.S.)
We are currently sequencing the coding fraction of the genome (the exome, ~2% of the genome) of two or more distant relatives (e.g. two affected cousins) from each family. Comparative disease concordant
pair-wise analyses, under different genetic models, are used to generate shortlists of novel, potentially disease-causing variants for disease segregation/transmission studies within each pedigree with multi-incident disease. Candidate variants are then followed up in many more ethically-specific and ethnically diverse patients and control subjects, to identify the same or other mutations in the same gene, and to prove pathogenicity.
Using this approach we recently identified two novel genes, vacuolar sorting protein 35 (VPS35) and receptor-mediated endocytosis 8 (DNAJ13), in which deficits result in PD. VPS35 and DNAJC13 work together in the same pathway, controlling the flux between endosomal degradation and recycling of specific membrane-associated proteins.
Our long term goal is to define the “PD genome‟ in order to identify novel genes and pathways for both neuroprotective and symptomatic therapies. Through genetics, we aim to accelerate the development of new treatments and to identify subgroups of patients most likely to benefit. The identification of novel genes/mutations is already starting to implicated biological networks in disease development, which are as relevant to idiopathic PD. These discoveries now provide the rational basis for cellular and animal models in which to develop and test novel therapies.