ATP13A2 Deficiency Induces a Decrease in Cathepsin D Activity, Fingerprint-Like Inclusion Body Formation, and Selective Degeneration of Dopaminergic Neurons

FEBS Lett. 2013 May 2;587(9):1316-25. doi: 10.1016/j.febslet.2013.02.046. Epub 2013 Mar 13.


Kufor-Rakeb syndrome (KRS) was originally described as an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia. ATP13A2 was identified as the causative gene in KRS. ATP13A2 encodes the ATP13A2 protein, which is a lysosomal type5 P-type ATPase, and ATP13A2 mutations are linked to autosomal recessive familial parkinsonism. Here, we report that normal ATP13A2 localizes in the lysosome, whereas disease-associated variants remain in the endoplasmic reticulum. Cathepsin D activity was decreased in ATP13A2-knockdown cells that displayed lysosome-like bodies characterized by fingerprint-like structures. Furthermore, an atp13a2 mutation in medaka fish resulted in dopaminergic neuronal death, decreased cathepsin D activity, and fingerprint-like structures in the brain. Based on these results, lysosome abnormality is very likely to be the primary cause of KRS/PARK9.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cathepsin D / metabolism*
  • Cell Line, Tumor
  • Dopaminergic Neurons / cytology*
  • Dopaminergic Neurons / enzymology
  • Dopaminergic Neurons / pathology
  • Endoplasmic Reticulum / metabolism
  • Gene Knockdown Techniques
  • Humans
  • Inclusion Bodies / metabolism*
  • Lysosomes / metabolism
  • Mutation
  • Oryzias / genetics
  • Protein Transport
  • Proton-Translocating ATPases / deficiency*
  • Proton-Translocating ATPases / genetics*


  • ATP13A2 protein, human
  • Cathepsin D
  • Proton-Translocating ATPases