PRKN Gene Function & Its Critical Role in Parkinson’s Pathogenesis

PRKN Gene Overview: Comparative Genomics (Human vs. Rodents)

Parkin Protein: E3 Ligase Mechanism and Pathogenic Mutations

Parkin, encoded by PRKN gene, is one of the largest human genes with a length of 1.38 million bp. The Prkn gene in mice and rats is also around 1.2 million bp in length. The human Parkin protein, an E3 ubiquitin ligase consisting of 465 amino acids, is responsible for attaching ubiquitin, a signal described as “the molecular kiss of death” to the targeted protein for recognition and breakdown by the protease. The human PRKN protein does not have much difference in length compared to the protein in mice and rats, however, they vary greatly in major RNA derivatives of PRKN. The length of major transcripts in humans are almost 2.7 times that of rats. However, the number of amino acid bases in the protein is roughly the same across these species.

PRKN is a recessively inherited gene of Parkinson's disease (PD); in other words, humans develop PD only when the gene is recessively homozygous. Figure 1 shows different structures and mutations of Parkin protein. The item on the left represents ubiquitin binding region (UBL), followed by linker region (Linker), ring finger domain 0 (RING0) and typical RBR structure (RING1-IBR-RING2), where the REP structure contains rich cysteine.

Figure 1: Human mutation sites in the population, where the red represents pathogenic mutation sites, and black indicates unknown effect. DOI: 10.3233/JPD-160989.

Figure 2: Role of Parkin in Parkinson's disease and cancer. DOI: 10.1007/s12035-018-0879-1

Under normal circumstances, Parkin (PARK2) can label CyclinE and other proteins with ubiquitin, and guide proteases to degrade them. However, when the protein-coding gene mutation causes abnormalities in the protein, it will not be able to perform the function of ubiquitination normally, thus resulting in the aggregation of some cyclins and other functional proteins. Additionally, it may cause abnormal proliferation in cells with mitotic conditions and apoptosis in neurons without mitotic conditions (Figure 3).

Figure 3: Quoted from DOI: 10.1007/s12035-018-0879-1

Tissue-Specific Expression: Beyond Neurodegeneration

Figure 4: mRNA relative expression of PRKN gene in humans and mice.

The expression of this gene in brain tissue and testis is significantly higher than that in other tissues. In addition, the expression of this gene is also high in human heart and kidney, even higher than that in human brain, where such gene is used to be studied. The expression of this gene in human adrenal glands is higher than the average (the expression is expressed by the normalized relative value rather than the direct RPKM data; such comparison is only limited to the same species rather than in between mice and human). Source: NCBI.

Since the first pathogenic gene of PD was identified in the 1990s, an increasing importance has been attached to the genetic influence on in the pathogenesis of PD.

Find more PD related mouse models in our selection of research-ready Cyagen Knockout Catalog Models.

References

1. Wahabi, K., Perwez, A. & Rizvi, M.A. Parkin in Parkinson’s Disease and Cancer: a Double-Edged Sword. Mol Neurobiol 55, 6788–6800 (2018). https://doi.org/10.1007/s12035-018-0879-1.

2. Truban, Dominika et al. ‘PINK1, Parkin, and Mitochondrial Quality Control: What Can We Learn About Parkinson’s Disease Pathobiology?’ 1 Jan. 2017 : 13 – 29.

3. Auluck PK, Caraveo G, Lindquist S. α-Synuclein: membrane interactions and toxicity in McGregor MM, Nelson AB. Circuit Mechanisms of Parkinson's Disease. Neuron. 2019;101(6):1042-1056.