Study Rationale: Recessively inherited forms of Parkinson’s disease (PD) caused by mutations on both copies of the genes PRKN and PINK1 are unique in many aspects. Age at onset is mainly before the age of 40 years. In the beginning, dystonia (involuntary muscle contractions) seems to be a commonly recognized feature that can raise difficulties in distinction from dopa-responsive dystonia. Over time, most patients develop early and marked levodopa-induced motor fluctuations and dyskinesias, although the course of the disease seems to progress slowly with rare development of dementia. In line with these clinical characteristics, histopathological findings in the brains of these patients show nigral degeneration but typically not the hallmark Lewy body pathology (composed of aggregates of the protein alpha-synuclein). Moreover, researchers debate vividly whether heterozygous mutations (only one mutation on one copy of these genes) may cause or increase the susceptibility for common and typical late-onset PD.
The proteins (PRKN, PINK1) that are built from these genes act in a cascade to protect neurons against oxidative stress by eliminating damaged mitochondria (energy reservoir of cells).
Hypothesis: An improved understanding of the contribution of parkin and PINK1 dysfunction in PD pathogenesis is an unmet need for the development of therapies targeting these proteins.
Study Design: To translate our understanding of the biology of these proteins into specific therapies and biomarkers for future trials, we will build a worldwide MJFF consortium focusing on the standardized collection of clinical data and biosamples (blood, urine, cerebrospinal fluid) from PRKN and PINK1 mutation carriers with and without PD.
Impact on Diagnosis/Treatment of Parkinson’s disease: The deep phenotyping of these samples will shed light on the mechanisms and targets that play a role in these genetic forms of PD. Importantly, this could also help to explore and translate molecular signatures related to these mitochondrial prototypes in the large group of sporadic people with PD in order to stratify these for molecular pathway-specific trials.
Next Steps for Development: Moreover, this consortium will be a unique source following a trial-ready cohort.