This report describes Parkinson disease 2 (PARK2, PD2), which is a subtype of Parkinson disease. PARK2 is inherited primarily as an autosomal recessive; heterozygotes may have increased susceptibility to late-onset disease. The human gene implicated in this disease is Parkin (PRKN, previously PARK2), which is an E3 ubiquitin ligase involved in mitochondrial maintenance and proteasome-dependent degradation of proteins. This gene is also associated with adenocarcinoma of lung, somatic (MIM:211980) and adenocarcinoma, ovarian, somatic (MIM:167000). There is a single fly ortholog, park, for which classical amorphic and hypomorphic alleles, RNAi-targeting constructs, and alleles caused by insertional mutagenesis have been generated.
Multiple different UAS constructs of the human Hsap\PRKN gene have been introduced into flies, including wild-type PRKN and genes carrying mutational lesions implicated in PRKN. Heterologous rescue (functional complementation) of assayed phenotypes of a Dmel\park null mutation has been demonstrated. Phenotypic assays using the human gene have allowed characterization of genetic interactions with candidate fly genes and transgenic human genes.
Variant(s) implicated in human disease tested (as transgenic human gene, PRKN): the Q311*, T240R, and R275W variant forms of the human gene have been introduced into flies. See the 'Disease-Implicated Variants table below. Results in flies do not support the hypothesis that the G328E variant is a pathogenic variant.
Animals carrying loss-of-function mutations in the Dmel\park gene are viable, but sterile; they exhibit muscle defects, locomotor defects and reduced lifespan. Cardiomyopathy is observed at elevated rates among Parkinson patients (Zesiewicz et al., 2004; pubmed:15465398); this aspect of the disease has also been investigated using park loss-of-function genotypes.
Therapeutic drug candidates and classes of deleterious compounds have been administered by feeding and tested using several different phenotypic assays. See the FlyBase chemical report for L-dopa (FBch0000146) and the Human Disease Model report 'Parkinson disease, susceptibility plus toxin exposure' (FBhh0001390).
[updated Mar. 2024 by FlyBase; FBrf0222196]
Parkinson disease (PD) is a neurodegenerative disease usually typified by slow onset in mid to late adulthood; there are also early-onset and juvenile forms of the disease. Symptoms worsen over time and include resting tremor, muscular rigidity, bradykinesia [abnormal slowness of movement], and postural instability [impaired balance and coordination]; additional symptoms may include postural abnormalities, dysautonomia [symptoms caused by malfunction of the autonomic nervous system], dystonic cramps, and dementia. Parkinson disease is the second-most common neurodegenerative disease (after Alzheimer disease), affecting approximately 1% of the population over 50 (Polymeropoulos et al., 1996, pubmed:8895469). [from MIM:168600; 2013.07.23]
Parkinson disease is described as early-onset disease if signs and symptoms begin before age 50. Early-onset cases that begin before age 20 may be referred to as juvenile-onset disease. [from Genetics Home Reference, GHR_condition:parkinson-disease, 2015.02.13]
[PARKINSON DISEASE 2, AUTOSOMAL RECESSIVE JUVENILE; PARK2](https://omim.org/entry/600116)
[PARKIN RBR E3 UBIQUITIN PROTEIN LIGASE; PRKN](https://omim.org/entry/602544)
Parkinson disease 2 is characterized by juvenile or early onset. Initially characterized by gait disturbances, progressing to slow movement, tremors and frozen gait; dementia is not typically observed; early death observed in some pedigrees. A distinguishing feature of this phenotype is a benefit from sleep with lessening of parkinsonian symptoms after awakening. (Matsumine et al., 1998, pubmed:9595984) [from MIM:600116; 2015.02.16]
Parkinson disease 2 exhibits an autosomal recessive pattern of transmission; shown to be caused by mutation(s) in the PARK2 gene. Heterozygous mutations in the PARK2 gene have been identified in some patients with later onset disease, raising the possibility that heterozygous mutations may confer increased susceptibility to the disease (Oliveira, et al., 2003, pubmed:12730996). The PARK2 gene is quite large: 12 exons spanning 1380kb (Asakawa et al., 2001, pubmed:11527378); it to maps to FRA6E, one of the most common fragile sites in the human genome (Smith et al., 1998, pubmed:9454904). [from MIM:600116 and MIM:602544; 2015.02.16]
At autopsy of Parkinson disease 2 sufferers, depigmentation of specific areas of the brain is typically observed, due to mild to severe loss of pigmented neurons; Lewy bodies are not typically observed (Mori et al., 1998, pubmed:9748052). [from MIM:600116; 2015.02.16]
PARK2 protein is a RING-domain-containing E3 ubiquitin-protein ligase involved in proteasome-dependent degradation of proteins. It is important for mitochondrial quality control by lysosome-dependent degradation of damaged mitochondria through autophagy, or mitophagy (summary by Yoshii, et al., 2011, pubmed:21454557). [from MIM:602544; 2015.02.16]
The first experimental evidence for the close functional link between PINK1 (PARK6) and Parkin (PARK2) came from work done in Drosophila (FBrf0193434, FBrf0193630, FBrf0191922). It is now known that these two proteins are primary effectors of mitophagy, a type of selective autophagy that targets damaged mitochondria. Conditions of mitochondrial stress (reduced mitochondrial membrane potential) lead to PINK1 accumulation; PINK1 recruits cytoplasmic Parkin to the mitochondrion; Parkin ubiquitinates proteins in the outer mitochondrial membrane, which targets the damaged mitochondrion for mitophagy (reviewed in Narendra, et al., 2012, pubmed:23125018). Many steps and regulatory components of this process are still uncharacterized; for a recent review of mitophagy and other mitochondrial quality control pathways, see Held and Houtkooper, 2015 (pubmed:26010263).
One to one: 1 human to 1 Drosophila.
High-scoring ortholog of human PRKN (1 Drosophila to 1 human). Dmel\park shares 43% identity and 59% similarity with human PRKN.
