Genetics of Parkinson's Disease: Mitochondrial Dysfunction Antibody Sampler Kit #30370

Parkinson’s disease (PD), the second most common neurodegenerative disease, is a progressive movement disorder characterized by rigidity, tremors, and postural instability. The pathological hallmark of PD is progressive loss of dopaminergic neurons in the substantia nigra of the ventral midbrain and the presence of intracellular Lewy bodies in surviving neurons of the brain stem (1). Mitochondrial dysfunction has been strongly implicated in the etiology of PD through both sporadic and familial cases. Several genes implicated in familial PD have been shown to play a role in mitochondrial dysfunction, including PRKN, PINK1, PARK7, PARK9, LRRK2, VPS35, and SNCA (2).  

α-Synuclein (SNCA) aggregation in the substantia nigra is a pathological hallmark of PD. This aggregation has several downstream consequences, including direct interaction with mitochondria, disrupting mitochondrial metabolism (3).

Parkin (PRKN) is an E3 ubiquitin ligase responsible for ubiquitinating damaged or unneeded proteins for degradation by proteasomes. PTEN induced putative kinase 1 (PINK1) is a mitochondrial serine/threonine kinase that phosphorylates parkin, recruiting it to the mitochondria where both play a key role in maintaining mitochondrial health (4). Mutations in PINK1 and PRKN are the two most common causes of autosomal recessive early-onset PD (5).

DJ-1 (PARK7) is a multifunctional protein involved in protecting the cell against oxidative stress. DJ-1 is known to translocate to the mitochondria in response to oxidative stress, where it may play a protective role against mitochondrial dysfunction. Loss-of-function mutations in PARK7 have been linked to recessive early-onset PD (6,7). ATP13A2 (PARK9) is a lysosomal type 5 P-type ATPase associated with autosomal recessive early-onset PD, which functions in the autophagy-lysosomal pathway. Mutations in PARK9 have been shown to impair mitochondrial function and disrupt zinc homeostasis in PD (8,9).

Leucine-rich repeat kinase 2 (LRRK2) is a widely expressed multifunctional kinase with several cellular implications in PD. Mutations in the LRRK2 gene have an established link to both autosomal dominant and sporadic PD. These mutations lead to an abnormal elevation in kinase activity with downstream contributions to PD pathology, including dopaminergic neuronal cell death, oxidative damage, and α-synuclein accumulation (10,11). LRRK2 may play a role in mitochondrial homeostasis; thus, mutations in LRRK2 may increase the cell's susceptibility to reactive oxygen species (12).

Vacuolar protein sorting-associated protein 35 (VPS35) is a component of the retromer complex responsible for endosomal trafficking. It has been shown that deficits and mutations in VPS35 cause mitochondrial fragmentation and cell death in dopaminergic neurons (13,14). Mutations in the VPS35 gene have been linked to late-onset autosomal PD (15).