The genetic architecture of mitochondrial dysfunction in Parkinson’s disease

Abstract

Mitochondrial impairment is a well-established pathological pathway implicated in Parkinson’s disease (PD). Defects of the complex I of the mitochondrial respiratory chain have been found in post-mortem brains from sporadic PD patients. Furthermore, several disease-related genes are linked to mitochondrial pathways, such as PRKN, PINK1, DJ-1 and HTRA2 and are associated with mitochondrial impairment. This phenotype can be caused by the dysfunction of mitochondrial quality control machinery at different levels: molecular, organellar or cellular. Mitochondrial unfolded protein response represents the molecular level and implicates various chaperones and proteases. If the molecular level of quality control is not sufficient, the organellar level is required and involves mitophagy and mitochondrial-derived vesicles to sequester whole dysfunctional organelle or parts of it. Only when the impairment is too severe, does it lead to cell death via apoptosis, which defines the cellular level of quality control. Here, we review how currently known PD-linked genetic variants interfere with different levels of mitochondrial quality control. We discuss the graded risk concept of the most recently identified PARK loci (PARK 17–23) and some susceptibility variants in GBA, LRRK2 and SNCA. Finally, the emerging concept of rare genetic variants in candidates genes for PD, such as HSPA9, TRAP1 and RHOT1, complete the picture of the complex genetic architecture of PD that will direct future precision medicine approaches.

Exploring mitochondrial cholesterol signalling for therapeutic intervention in neurological conditions

“…Within the context of mitochondrial dysfunction, classically, the research on Parkinson's disease (PD) has focussed on the deficiencies in quality control regulation of mitochondria by autophagy (Larsen, Hanss, & Kruger, 2018). However, disrupted cholesterol dynamics are also associated with established molecular features of PD (see Arenas, Garcia-Ruiz, & Fernandez-Checa, 2017).…”

Parkinson’s disease phenotypes in patient specific brain organoids are improved by HP-β-CD treatment

“…Among these, PINK1 is involved in regulating mitochondrial function and morphology by quarantining damaged mitochondria before their degradation as well as triggering the process of mitophagy (Ashrafi & Schwarz, 2012). The fact that individuals with biallelic pathogenic variants in PINK1 develop PD, shows that an altered mitochondrial function, morphology, and degradation are linked to its pathogenesis (Larsen et al, 2018).…”

Special issue “Parkinson’s disease”

“…In this issue, current concepts of the complex genetic architecture of PD are reviewed in the contribution by Billingsley et al (2018), emphasizing that those networks that have originally been based on the identification of rare Mendelian mutations causing hereditary forms of PD are also playing a major role in the common sporadic forms of the disease. Each of the major Mendelian genes turned out to lead to distinct pathways to disease that are described in depth in this issue: loss of function mutations in parkin and PINK1 cause autosomal-recessive PD with early onset by a disruption of mitochondrial quality control systems (Larsen et al 2018); mutations in LRRK2, the most common cause of autosomal-dominant PD, are thought to lead to increases of the kinase function of the encoded multidomain protein, thereby disrupting crucial pathways of cytoskeletal integrity and organelle transport (Price et al 2018). Heterozygous variants in the GBA gene, encoding the lysosomal enzyme glucocerebrosidase, were found to be the most common genetic risk factor for PD in many populations (Sidransky et al 2009).…”