Mitochondrial dysfunction plays a key role in Parkinson’s disease (PD), but the underlying molecular mechanisms involved are less well known. Using whole‐exome sequencing data from over 1000 patients with idiopathic PD, researchers assessed the enrichment of rare and damaging genetic variants on groups of genes controlling specific mitochondrial functions.1,2
Although no single gene significance was found among 868 genes in 28 pathways studied, a significant polygenic enrichment of rare, non-synonymous variants in the gene-set encoding the pathway of mitochondrial DNA maintenance was found, which relates to the progression of both motor and non-motor features.
Multiple genetic variations are linked to impairment of mitochondrial DNA homeostasis - a key mechanism in the pathogenesis of PD - and may explain part of the disorder's “missing heritability.”
These results show that the enrichment of rare inherited variation in the pathway controlling mitochondrial DNA replication and repair influences the risk of PD and that features of disease progression are impacted by genetic variation. This polygenic enrichment may contribute to the impairment of mitochondrial DNA homeostasis, thought to be a key mechanism in the pathogenesis of PD, and explain part of the disorder's “missing heritability.”
Genetic link to evolution of prodromal PD
GBA mutations are the most frequent risk factor for PD. Their link to the development of PD was evaluated in a longitudinal study examining prodromal clinical features in a group of GBA mutation-positive individuals (Gaucher disease type 1 and Het GBA carriers) at risk of developing PD.3 Over the 6 years, GBA mutation-positive subjects showed a worsening in motor and non-motor prodromal PD features with significant deterioration of dysautonomic functions, sleep disorders, motor performance and depression. Notably, the control group also showed a worsening of parkinsonian features over the study period, but to a lesser extent.
GBA mutations – a frequent risk factor for PD – are linked to development of motor and non-motor features in prodromal PD.
Cognitive decline linked to shorter life expectancy in PD
Cognitive function is thought to be a good indicator for survival in PD. A 20-year follow-up of the Trondheim PD cohort of 1276 patients found high rates of cognitive decline within the first 15 years of disease (MoCA score <26) among 84% of patients.4 Median survival time was significantly shorter among patients showing signs of cognitive decline, with an average reduction in median survival time of 7 years (5 vs 12 years after a 15-year observation period).
Poor cognitive function reduces life expectancy in PD by approximately 7 years
Diagnostic utility of CSF NfL in atypical PD
Cerebrospinal fluid (CSF) concentrations of neurofilament light (NfL) may be a useful biomarker for differentiating PD from atypical parkinsonian syndromes (APS). Among 147 patients with a working diagnosis of APS, patients subsequently diagnosed with PD at the 25-month follow-up had significantly lower CSF NfL compared to patients fulfilling the criteria for multiple system atrophy (MSA) and progressive supranuclear palsy (PSP).5 Consequently, CSF NfL may be useful in differentiating patients with PD from patients with MSA and PSP, even when PD patients clinically present phenotypes mimicking APS in the early stages of disease.