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This report describes Parkinson disease 6 (PARK6, PD6), which is a subtype of Parkinson disease; PARK6 is inherited primarily as an autosomal recessive. The human gene implicated in this disease is PINK1, which is mitochondrially located serine/threonine kinase with key roles in mitochondrial maintenance and in the function of mitochondrial complex I. There is a single fly ortholog, Pink1, 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\PINK1 gene have been introduced into flies, including wild-type PINK1 and variants carrying compromising mutational lesions. Heterologous rescue (functional complementation) of all assayed phenotypes of a Dmel\Pink1 null mutation has been demonstrated. Phenotypic assays using the human gene have allowed characterization of genetic interactions with other genes implicated in Parkinson disease.
Variant(s) implicated in human disease tested (as transgenic human gene, PINK1): the G309D variant form and a C-terminal truncated variant of the human gene have been introduced into flies. Variant(s) implicated in human disease tested (as analogous mutation in fly gene): G426D in the fly Pink1 gene (corresponds to G309D in the human PINK1 gene); L464P in the fly Pink1 gene (corresponds to L347D in the human PINK1 gene). See the 'Disease-Implicated Variants' table below.
Animals carrying loss-of-function mutations in the Dmel\Pink1 gene are viable, but male-sterile and partially female-sterile; they exhibit neuroanatomy defects, locomotor defects and reduced lifespan.
Therapeutic drug candidates and classes of deleterious compounds have been administered by feeding and tested using several different phenotypic assays. See also the FlyBase chemical report for L-dopa (FBch0000146).
[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 6, AUTOSOMAL RECESSIVE EARLY-ONSET; PARK6](https://omim.org/entry/605909)
[PTEN-INDUCED KINASE 1; PINK1](https://omim.org/entry/608309)
Parkinson disease 6 is characterized by typical symptoms of Parkinson disease (described above); in some cases, symptoms show a pattern of sleep benefit (typical of PARK2). Early onset is typically observed; disease progression is usually slow. (Albanese et al., 2005, pubmed:15955954). Although most patients with PARK6 have features similar to those of PARK1, a subset demonstrate features similar to those of PARK2. [from MIM:605909; 2015.02.16]
Parkinson disease 6 typically exhibits an autosomal recessive pattern of transmission; shown to be caused by mutation(s) in the PINK1 gene. A subset of patients has been reported with heterozygous mutations in the PINK1 gene. [from MIM:605909; 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).
The PINK1 gene encodes a mitochondrially located serine/threonine kinase (Poole et al., 2008, pubmed:18230723). The PINK1 protein plays a role in maintenance of mitochondria by mediating PRKN protein recruitment to damaged mitochondria (Chen and Dorn, 2013, pubmed:23620051). It may also play an enzymatic role in mitochondrial complex I: specific loss-of-function mutants display a decrease in mitochondrial membrane potential (Morais et al., 2014, pubmed:24652937). [from MIM:608309; 2015.02.16]
One to one: 1 human to 1 Drosophila.
Ortholog of human PINK1 (1 Drosophila to 1 human). Dmel\Pink1 shares 29% identity and 42% similarity with human PINK1.
