Atp13a2 Knockout mouse models

Atp13a2, ortholog of human ATP13A2 (PARK9), encodes a P5B-type transport ATPase resident in late endosomes and lysosomes that exports polyamines, principally spermine, from the lumen to the cytosol using an N-terminal lipid-binding domain that recognizes phosphatidic acid and phosphoinositides for membrane targeting. Recessive truncating and misfolding alleles cause Kufor-Rakeb juvenile parkinsonism and neuronal ceroid lipofuscinosis, with loss of function producing lysosomal alkalinization, impaired cathepsin maturation, spermine-driven lysosomal rupture, and secondary accumulation of α-synuclein and lipofuscin. Conditional nulls crossed to Dat-Cre or Slc6a3-Cre isolate dopaminergic cell-autonomous degeneration, whereas a patient missense knockin distinguishes catalytic failure from ER retention and degradation of misfolded protein, and humanization supports chaperone or antisense screening against the human coding sequence. The paralogs Atp13a3, Atp13a4 and Atp13a5 transport overlapping polyamine substrates in other compartments, so quantify them before interpreting a mild null; age animals well past twelve months for lipofuscin and gliosis endpoints.

Atp13a2 null animals are straightforward to genotype and phenotype when survival is acceptable. They remain a standard background for pharmacology, biomarker, and rescue studies.