The contribution of Parkin, PINK1 and DJ‐1 genes to selective neuronal degeneration in Parkinson's disease

Abstract

Parkinson's disease (PD) is characterised by selective and severe degeneration of the substantia nigra pars compacta and the locus coeruleus (LC), which underlies the most prominent symptoms. Although α‐synuclein accumulation has long been established to play a causal role in the disease, it alone cannot explain the selective degenerative pattern. Recent evidence shows that the selective vulnerability could arise due to the large presence of cytosolic catecholamines and Ca 2+ ions in the substantia nigra pars compacta and LC specifically that can be aberrantly affected by α‐synuclein accumulation. Moreover, each has its own toxic potential, and disturbance of one can exacerbate the toxic effects of the others. This presents a mechanism unique to these areas that can lead to a vicious degenerative cycle. Interestingly, in familial variants of PD, the exact same brain areas are affected, implying the underlying process is likely the same. However, the exact disease mechanisms of many of these genetic variants remain unclear. Here, we review the effects of the PD‐related genes Parkin, PINK1 and DJ‐1. We establish that these mutant varieties can set in motion the same degenerative process involving α‐synuclein, cytosolic catecholamines and Ca 2+ . Additionally, we show indications that model organisms might not accurately represent all components of this central mechanism, explaining why Parkin, PINK1 and DJ‐1 model organisms often lack a convincing PD‐like phenotype.

The Parkinson’s disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release

“…In addition to SNCA, mutations in several other genes have been identified that cause rare, familial forms of PD. These genes are primarily involved in the autophagic clearance of intracellular aggregates or damaged organelles, especially mitochondria ( 5 – 8 ). Genome-wide association studies (GWAS) have also identified common SNPs in several genes related to endolysosomal function, such as GBA and LRRK2, that are associated with increased risk of PD ( 8 – 11 ).…”

Global ubiquitylation analysis of mitochondria in primary neurons identifies physiological Parkin targets following activation of PINK1

“…Both sites are highly conserved and lie close to Cys106 that is modified under oxidative stress conditions, thereby stimulating DJ1 recruitment from the cytosol to the mitochondria (Figure S13A) (Canet-Aviles et al, 2004). Patients with DJ1 mutations resemble PINK1 and Parkin patients (van der Vlag et al, 2020), however, we observed that the reduction of DJ1 ubiquitylation at Lys 93 was PINK1 independent (Figure S13B) and in future work it will be interesting to determine the mechanism of the functional impact of DJ1 ubiquitylation in the context of mitophagic signalling.…”

The Promise and Challenges of Developing miRNA-Based Therapeutics for Parkinson’s Disease

“…Such targets include, of course, α-Syn, but extend to a panoply of mechanisms that might impact upon α-Syn, either in all or subsets of the PD population, these include oxidative stress [18], LRRK2 [19], apoptosis [20], neuroinflammation [21], misfolding proteins [22], age [2], melanin [23] and iron accumulation [24]. The most attractive of these targets also have support from genetic studies, and include LRRK2 [25], parkin, PINK1 [26] and GBA [27]. MicroRNAs are also emerging targets that have gained increased attention in neurodegenerative disorders, including PD [28].…”