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General Information
Name
Parkinson disease 6, early-onset
FlyBase ID
FBhh0000009
Disease Ontology Term
Parent Disease
Overview

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).

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. Physical interactions of the Dmel\Pink1 protein product have been described; see below and in the Pink1 gene report. Phenotypic assays using the fly gene have allowed characterization of genetic interactions.

Therapeutic drug candidates and classes of deleterious compounds have been administered by feeding and tested using several different phenotypic assays.

[updated Dec. 2016 by FlyBase; FBrf0222196]

Disease Summary Information
Parent Disease Summary: Parkinson disease
Symptoms and phenotype

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 OMIM: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]

Specific Disease Summary: Parkinson disease 6, early-onset
OMIM report

[PARKINSON DISEASE 6, AUTOSOMAL RECESSIVE EARLY-ONSET; PARK6](https://omim.org/entry/605909)

Human gene(s) implicated

[PTEN-INDUCED KINASE 1; PINK1](https://omim.org/entry/608309)

Symptoms and phenotype

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 OMIM:605909; 2015.02.16]

Genetics

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 OMIM:605909; 2015.02.16]

Cellular phenotype and pathology
Molecular information

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 OMIM:608309; 2015.02.16]

External links
Disease synonyms
AR-JP
PARK6
Parkinson's disease
Parkinson disease
Parkinson disease 6
Parkinson disease 6, autosomal recessive early-onset
Parkinson disease 6, early onset
PD
PD6
Ortholog Information
Human gene(s) in FlyBase
Human gene (HGNC)
D. melanogaster ortholog (based on DIOPT)
Comments on ortholog(s)

One to one: 1 human to 1 Drosophila.

Other mammalian ortholog(s) used
    D. melanogaster Gene Information (1)
    Gene Snapshot
    PTEN-induced putative kinase 1 (Pink1) is the ortholog of human PINK1, a gene mutated in autosomal recessive Parkinson's disease. Pink1 encodes a mitochondrially targeted Ser-Thr kinase. It has been linked to a number of cellular functions including altering mitochondrial dynamics, the autophagic degradation of dysfunctional mitochondria, and the proper function of Complex I of the electron transport chain. [Date last reviewed: 2018-10-11]
    Gene Groups / Pathways
    Comments on ortholog(s)

    Ortholog of human PINK1 (1 Drosophila to 1 human). Dmel\Pink1 shares 29% identity and 42% similarity with human PINK1.

    Orthologs and Alignments from DRSC
    DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans
    Other Genes Used: Viral, Bacterial, Synthetic (0)
      Summary of Physical Interactions (11 groups)
      protein-protein
      Interacting group
      Assay
      References
      anti tag coimmunoprecipitation, western blot, anti bait coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      enzymatic study, western blot
      pull down, anti tag western blot, anti bait coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti tag coimmunoprecipitation, anti tag western blot
      anti bait coimmunoprecipitation, western blot
      RNA-RNA
      Interacting group
      Assay
      References
      quantitative reverse transcription pcr, luminiscence technology
      Alleles Reported to Model Human Disease (Disease Ontology) (18 alleles)
      Models Based on Experimental Evidence ( 9 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 13 )
      Allele
      Disease
      Interaction
      References
      is ameliorated by mask10.22
      is ameliorated by maskEY13048
      is ameliorated by maskHMS01045
      is ameliorated by maskKK100529
      is exacerbated by ShmtGD8851
      is ameliorated by Lrrke03680
      is ameliorated by ParpCH1
      is ameliorated by STUB1UAS.cCa
      is ameliorated by Opa1s3475
      is ameliorated by Opa1f02779
      is ameliorated by mAcon11
      is ameliorated by GstO2A.UAS
      is ameliorated by Ucp4AUAS.cWa
      is ameliorated by dj-1βUAS.cMa
      is ameliorated by dj-1βC45A.UAS
      is ameliorated by DJ-1αUAS.cUa
      is ameliorated by Pink1UAS.cUa
      is ameliorated by MiroJF02775
      is exacerbated by MiroUAS.cGa
      is ameliorated by miltJF03022
      is ameliorated by KhcJF01939
      is ameliorated by MiroKK102189
      is ameliorated by foxoUAS.cKd
      is ameliorated by Sirt1EP2300
      is ameliorated by Sirt1UAS.cGa
      is ameliorated by Sod2UAS.cUa
      is ameliorated by cluUASp.cSa
      is ameliorated by Trap1D6
      is ameliorated by Trap1EY21851
      is ameliorated by PEKGD5584
      is ameliorated by ND-42SA.UAS
      is exacerbated by heix1
      is exacerbated by heix2
      is exacerbated by heixk11403
      is exacerbated by heixNP5301
      is ameliorated by Pgam5NP0568
      is ameliorated by Pgam51
      is ameliorated by Trap1UAS.cCa
      is exacerbated by rictorJF01370
      is ameliorated by trcS292E.UAS.L
      is ameliorated by rictorUAS.cHa
      is ameliorated by trcL.UAS
      is NOT ameliorated by RetMEN2B.UAS
      is ameliorated by RetMEN2B.UAS
      is ameliorated by RetMEN2B.UAS
      is NOT ameliorated by RetMEN2B.UAS
      is ameliorated by TER94UAS.cRa
      is ameliorated by dnkUAS.cLa
      is exacerbated by cluGD13926
      is exacerbated by cluKK108024
      is ameliorated by trcshort.UAS
      is exacerbated by rictorJF01370
      is exacerbated by rictorΔ2
      is ameliorated by rictorUAS.cHa
      is ameliorated by trcL.UAS
      is ameliorated by trcS292E.UAS.L
      is exacerbated by Sin1unspecified
      is exacerbated by rictorJF01086
      is ameliorated by trcT453E.UAS.L
      is exacerbated by Atg1K38Q.UAS
      is ameliorated by Atg1UAS.cSa
      is exacerbated by Atg13NIG.7331R
      is exacerbated by Atg18aVDRC.cUa
      is exacerbated by Atg3VDRC.cUa
      is ameliorated by CatUAS.cUa
      is ameliorated by GstS1UAS.cUa
      is ameliorated by PHGPxUAS.cUa
      is ameliorated by RpS9VDRC.cUa
      is exacerbated by S6kSTDE.UAS
      is exacerbated by S6kSTDETE.UAS
      is exacerbated by S6kTE.UAS
      is exacerbated by S6kUAS.cUa
      is ameliorated by S6kVDRC.cUa
      is ameliorated by Sod1UAS.cUa
      is ameliorated by ThorUAS.cMa
      is exacerbated by eIF4E1UAS.cRa
      is ameliorated by parkUAS.Tag:HA
      Models Based on Experimental Evidence ( 0 )
      Allele
      Disease
      Evidence
      References
      Modifiers Based on Experimental Evidence ( 3 )
      Alleles Representing Disease-Implicated Variants
      Genetic Tools, Stocks and Reagents
      Sources of Stocks
      Contact lab of origin for a reagent not available from a public stock center.
      Bloomington Stock Center Disease Page
      Selected mammalian transgenes
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila transgenes
      Allele
      Transgene
      Publicly Available Stocks
      RNAi constructs available
      Allele
      Transgene
      Publicly Available Stocks
      Selected Drosophila classical alleles
      Allele
      Allele class
      Mutagen
      Publicly Available Stocks
      loss of function allele
      P-element activity
      loss of function allele
      P-element activity
      References (174)