Kolicheski, Ana

Parkinson’s disease (PD) by its common understanding is a late-onset sporadic movement disorder. However, there is a need to recognize not only the fact that PD pathogenesis expands beyond (or perhaps to) the brain but also that many early-onset patients develop motor signs before the age of 50 years. Indeed, studies have shown that it is likely the protein aggregation observed in the brains of patients with PD precedes the motor symptoms by perhaps a decade. Studies on early-onset forms of PD have shown it to be a heterogeneous disease with multiple genetic and environmental factors determining risk of different forms of disease. Genetic and neuropathological evidence suggests that there are α-synuclein centric forms (e.g., SNCA genomic triplication), and forms that are driven by a breakdown in mitochondrial function and specifically in the process of mitophagy and clearance of damaged mitochondria (e.g., PARKIN and PINK1 recessive loss-of-function mutations). Aligning genetic forms with recognized environmental influences will help better define patients, aid prognosis, and hopefully lead to more accurately targeted clinical trial design. Work is now needed to understand the cross-talk between these two pathomechanisms and determine a sense of independence, it is noted that autopsies studies for both have shown the presence or absence of α-synuclein aggregation. The integration of genetic and environmental data is critical to understand the etiology of early-onset forms of PD and determine how the different pathomechanisms crosstalk.

Loss of either PINK1 or PRKN causes an early onset Parkinson’s disease (PD) phenotype. Functionally, PINK1 and PRKN work together to mediate stress-activated mitochondrial quality control. Upon mitochondrial damage, PINK1, a ubiquitin kinase and PRKN, a ubiquitin ligase, decorate damaged organelles with phosphorylated ubiquitin for sequestration and degradation in lysosomes, a process known as mitophagy. While several genetic mutations are established to result in loss of mitophagy function, many others have not been extensively characterized and are of unknown significance. Here, we analyzed a set of twenty variants, ten in each gene, focusing on understudied variants mostly from the Parkinson’s progressive marker initiative, with sensitive assays to define potential functional deficits. Our results nominate specific rare genetic PINK1 and PRKN variants that cause loss of enzymatic function in line with a potential causative role for PD. Additionally, we identify several variants with intermediate phenotypes and follow up on two of them by gene editing midbrain-derived neuronal precursor cells. Thereof derived isogenic neurons show a stability defect of the rare PINK1 D525N mutation, while the common PINK1 Q115L substitution results in reduced kinase activity. Our strategy to analyze variants with sensitive functional readouts will help aid diagnostics and disease treatment in line with current genomic and therapeutic advances.

Abstract A number of efforts are underway to better understand the role of genetic variation in successful aging and longevity. However, to date, only two genes have been consistently associated with longevity in humans: APOE and FOXO3, with the APOE ɛ2 allele also protective against dementia. Recently, using an exome-wide SNP array approach, a missense variant CLEC3B c.316G>A (rs13963 p.S106G) was reported to associate with longevity in two independent cohorts of Japanese and Chinese participants. Interestingly, CLEC3B p.S106G is more frequent in Caucasian populations. Herein, we examined the frequency of CLEC3B p.S106G in a Caucasian series of 1,483 neurologically healthy individuals with a specific subset >80 years of age. Although our findings do not support an association between CLEC3B p.S106G and aging without neurological disease (p = .89), we confirmed the association between the APOE ε2 allele and better survival without neurological disease (p = .001). Further assessment of healthy aged cohorts that retain intact neurological function will be critical to understand the etiology of neurodegenerative disease and the role of age at risk.