This report describes 'neurodegenerative disorders, ATP13A2-related'. Both diseases covered by this report, Kufor-Rakeb syndrome (or Parkinson disease 9, MIM:606693, FBhh0000987) and spastic paraplegia 78 (MIM: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 αtubulin 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]
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 MIM:606693, MIM:617225; 2019.03.19]
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]
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).
Many to one: 4 human to 1 Drosophila. The human genes are ATP13A2, ATP13A3, ATP13A4, and ATP13A5.
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.
