Although most cases of Parkinson’s Disease (PD) are idiopathic, there is a small fraction of cases that have known genetic factors – presented in diagnoses of familial PD. Roughly 5% -15% of PD cases are due to a mutation occurring in one of several specific genes, commonly designated as PARK genes (due to their association with PD). The genetic mutations that lead to PD can be transmitted in either an autosomal-recessive or autosomal-dominant pattern, and can contribute to the pathogenesis of either familial or sporadic PD depending on the specific gene mutated.
In this brief review, we will discuss the primary genes associated with Parkinson’s disease (PD) as well as some of their implications in additional disease pathologies. Read on to discover more about the PARK genes, TRB3, and some of the established mouse models for researching these targets in vivo.
While the role of parkin in development of PD is described in the table below, researchers have recently identified the role of parkin-mediated mitophagy in the protective effect of polydatin in sepsis-induced acute kidney injury (SI-AKI). Cyagen provided the Parkin -/- mice (C57BL/6) used to establish a sepsis model by caecal ligation and puncture (CLP) – which were treated with polydatin or vehicle (DMSO). Given that parkin-mediated mitophagy is known to involve the translocation of parkin from the cytosol to the mitochondria, this study separated the mitochondrial and cytosolic fractions of renal cells for analysis. Mice treated with polydatin revealed an increase of parkin in mitochondria, which was associated with a decrease in cytosolic levels of parkin – indicating that polydatin promotes translocation of Parkin.
Parkin’s involvement in polydatin-mediated mitophagy was further confirmed through the examination of mitophagy activity in Parkin-/- mice. The polydatin-treated Parkin-/- mice demonstrated significantly higher levels of mitochondrial markers TOM20 and TIM23, compared to polydatin-treated wild-type mice. Collectively, these findings suggest that the absence of parkin hinders polydatin-mediated mitophagy.1
SNCA codes for alpha-synuclein (α- synuclein) protein, the main component of Lewy bodies (LBs) – the primary biomarker for PD. α‐synuclein transgenic Drosophila and mouse models exhibited progressive locomotor dysfunction and loss of dopaminergic neurons, mimicking the phenotype of Parkinson’s disease. Different groups with familial PD have presented duplications and triplications of he SNCA locus, as well as missense mutations, although these are rarer. The expression level of α-synuclein correlates with disease onset and progression – SNCA gene triplication is shown to advance earlier and more quickly than duplication. Surprisingly, gene multiplications have also been found in asymptomatic carriers, indicating either incomplete or age-dependent penetrance.
Studies indicate that the DJ-1 protein encoded by PARK7 has several functions, but none are fully understood. DJ-1 is distributed in many tissues and organs, including the brain, and may help protect brain cells from oxidative stress. Additionally, DJ-1 may serve as a chaperone molecule or play a role in RNA production and processing activities.
Genes Associated with Familial Parkinson’s Disease (PD)
|HGNC Gene Symbol||Gene Name||Encoded Protein & Function||Mutations||Associated Symptoms & Phenotypes||Inheritance||Related Catalog Models|
|PARK1||SNCA||Alpha-synuclein||Missense mutations chromosome 4q21: A53T, A30P; Duplications; Triplications||α‐synuclein serves as a substrate for parkin; tau inclusions; Neuroimaging features consistent with those observed in idiopathic PD||Dominant||Snca KO Mouse Sncaip KO Mouse|
|PARK4||Haplotype on chromosome 4p||Postural tremor; asymmetrical limb ‘heaviness’ and rigidity||Dominant|
|PARK2||Parkin (PRKN)||E3 ubiquitin ligase||>70 mutations identified||Classical parkinsonism; dystonia; reduced uptake of dopamine tracer||Recessive||Park2 KO Mouse|
|PARK5||Ubiquitin C-terminal hydroxylase L1 (UCH-L1)||UCH‐L1 enzyme||I93M||Dopa-responsive parkinsonism, resembling idiopathic PD; reduced catalytic activity of UCH-L1 enzyme; Lewy bodies stain positive for UCH-L1||Dominant|
|PARK6||PINK1||PTEN induced putative kinase 1||>70 mutations identified - many of which alter or eliminate the kinase domain, leading to loss of protein function||Early-onset parkinsonism; slow progression of symptoms; tremor; no dystonia observed.||Recessive||Pink1 KO Mouse|
|PARK7||DJ-1||DJ1 protein||Homozygous deletion; Homozygous L166P mutation||Variable disease severity; slow progression of symptoms||Recessive||Park7 KO Mouse|
|PARK8||LRRK2||Dardarin; leucine rich repeat kinase 2||Heterozygous pathogenic variant identified||Lacks lewy bodies typical of PD; incomplete penetrance of haplotype||Dominant||Lrrk2 KO Mouse|
|PARK9||ATP13A2||ATPase type 13A2||Multiple isoforms identified||Kufor-Rakeb syndrome; spasticity, dementia, and supranuclear gaze paralysis||Recessive||Atp13a2 KO Mouse|
In vivo investigation has revealed that knockout (KO) of Tribbles homolog 3 (TRB3) improved the behavior impairment in MPTP-induced PD mice. In addition to the whole-body TRB3 KO mouse model (generated by Cyagen), researchers established an MPP+-induced PD cellular model to examine the effects of transfection with TRB3-shRNA. In this cellular model of PD, TRB3 was markedly upregulated through the ATF4/CHOP pathway. In contrast, the in vitro “knockdown of TRB3 significantly decreased the MPP+-induced reduction of cell viability, augment of cell apoptosis and accumulation of ROS, inhibited the phosphorylation of p38 and JNK, and promoted the phosphorylation of AKT.” Overall, it was shown that TRB3 knockdown has a neuroprotective effect across both cellular and mouse models of PD, through regulation of MAPK and AKT signaling pathways.2
Cyagen has also generated a TRB3 KO mouse model available to order from our catalog.
Citations (Animal Models):