Collectively, the present study demonstrates that disease-associated homozygous and heterozygous missense mutations in ATP13A2 exhibit differential pathogenic effects on protein stability, subcellular localization, ATPase activity and neuronal phenotypes, thereby providing support for a pathogenic loss-of-function mechanism for these mutations in precipitating early-onset parkinsonism. This evidence concerns the gene DNAH8 and Parkinsonism.