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General Information
neurodegenerative disorders, ATP13A2-related
FlyBase ID
Disease Ontology Term
Parent Disease

This report describes 'neurodegenerative disorders, ATP13A2-related'. Both diseases covered by this report, Kufor-Rakeb syndrome (or Parkinson disease 9, OMIM: 606693, FBhh0000987) and spastic paraplegia 78 (OMIM:617225, FBhh0000988) exhibit autosomal recessive inheritance. The gene implicated in these diseases, ATP13A2, encodes a lysosomal transmembrane ATPase that is required for a proper lysosomal and mitochondrial maintenance. There is a single orthologous gene in Drosophila, anne, for which an RNAi targeting construct and alleles caused by insertional mutagenesis have been generated. Dmel\anne is also orthologous to human ATP13A3, ATP13A4, and ATP13A5.

The human ATP13A2 gene has not been introduced into flies.

Animals with knockdown of Dmel\anne, effected by RNAi in either all neurons or in brain, have been characterized for HDAC6 activity, lysosome function, and autophagosome function. ATP13A2 knockdown reduces HDAC6 histone deacetylase activity, increases ╬▒tubulin acetylation, and disrupts lysosome-autophagosome fusion; the lysosomal abnormalities are suppressed by overexpression of HDAC6. Formation of inclusion body-like protein aggregates in brain of young adult flies is observed and increases as the animals age. It is postulated that impaired ATP13A2/HDAC6 signaling contributes to neural pathogenesis by disrupting clearance of protein aggregates and damaged mitochondria.

[updated Mar. 2019 by FlyBase; FBrf0222196]

Disease Summary Information
Disease Summary: neurodegenerative disorders, ATP13A2-related
OMIM report
Human gene(s) implicated
Symptoms and phenotype

Biallelic mutation in the ATP13A2 gene causes spastic paraplegia 78 (SPG78) and Kufor-Rakeb syndrome (KRS), neurodegenerative disorders with overlapping features. Patients with KRS have earlier onset and prominent parkinsonism. Patients with SPG78 have later onset and prominent spasticity, but rarely parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (summary by Estrada-Cuzcano et al., 2017; pubmed:28137957). [from OMIM:606693, OMIM:617225; 2019.03.19]

Cellular phenotype and pathology
Molecular information

ATP13A2 encodes a lysosomal transmembrane P5B-type ATPase. ATP13A2 loss leads to lysosomal abnormalities, impaired mitochondrial function, increased metal sensitivity, and increased sensitivity to ER stress. It has been tied to autophagy and other cellular features of neurodegeneration (FBrf0241154 and references cited therein).

ATP13A2 encodes a member of the P5 subfamily of ATPases which transports inorganic cations as well as other substrates. The encoded ATPase plays a role in intracellular cation homeostasis and the maintenance of neuronal integrity; it is required for a proper lysosomal and mitochondrial maintenance. [Gene Cards, ATP13A2; 2019.03.19]

External links
Disease synonyms
atypical Parkinsonism
Ortholog Information
Human gene(s) in FlyBase
    Human gene (HGNC)
    D. melanogaster ortholog (based on DIOPT)
    Comments on ortholog(s)

    Many to one: 4 human to 1 Drosophila. The human genes are ATP13A2, ATP13A3, ATP13A4, and ATP13A5.

    Other mammalian ortholog(s) used
      D. melanogaster Gene Information (1)
      Cellular component (GO)
      Gene Groups / Pathways
      Comments on ortholog(s)

      Moderate- to high-scoring ortholog of human ATP13A2, ATP13A3, ATP13A4, and ATP13A5 (1 Drosophila to 4 human). Dmel\anne shares 35-38% identity and 52-56% similarity with the human genes.

      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 (1 groups)
        Interacting group
        anti bait coimmunoprecipitation, quantitative reverse transcription pcr
        Alleles Reported to Model Human Disease (Disease Ontology) (3 alleles)
        Models Based on Experimental Evidence ( 3 )
        Modifiers Based on Experimental Evidence ( 1 )
        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
        Publicly Available Stocks
        Selected Drosophila transgenes
        Publicly Available Stocks
        RNAi constructs available
        Publicly Available Stocks
        Selected Drosophila classical alleles
        Allele class
        Publicly Available Stocks
        References (5)