Comprehensive review of ATP13A2 structure, function, pathology, and cross-species cellular and animal models, linking lysosomal polyamine, metal cation, and calcium dysregulation to ATP13A2-linked neurodegeneration including Kufor-Rakeb syndrome.

By consolidating mechanistic insights and preclinical models that tie lysosomal dysfunction and metal/polyamine homeostasis to neuronal loss, the paper highlights actionable pathways and experimental systems that can be used for target validation, biomarker development, and therapeutic screening…

ATP13A2 is a lysosomal P5-ATPase highly expressed in the central nervous system, regulating polyamine, metal cation, and calcium homeostasis. Loss-of-function mutations cause an autosomal recessive juvenile form of Parkinson's disease called Kufor-Rakeb syndrome and other neurodegenerative disorders. Since the first clinical discovery of the Kufor-Rakeb syndrome, numerous ATP13A2-related models have emerged, leading to significant advances in understanding the physiology and pathophysiology of this protein. This review summarizes ATP13A2 structure, function, pathology, and insights gained from cellular and animal models, highlighting their value for elucidating disease mechanisms and therapeutic development across species and experimental systems, relevant to neurodegeneration research broadly.