Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase

Topic: Disease mechanisms in lab and animal studies

Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders. Although the complex molecular pathophysiology of neurodegeneration is largely unknown, major advances have been achieved by elucidating the genetic defects underlying mendelian forms of these diseases. This has led to the discovery of common pathophysiological pathways such as enhanced oxidative stress, protein misfolding and aggregation and dysfunction of the ubiquitin-proteasome system. Here, we describe loss-of-function mutations in a previously uncharacterized, predominantly neuronal P-type ATPase gene, ATP13A2, underlying an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia (PARK9, Kufor-Rakeb syndrome). Whereas the wild-type protein was located in the lysosome of transiently transfected cells, the unstable truncated mutants were retained in the endoplasmic reticulum and degraded by the proteasome. Our findings link a class of proteins with unknown function and substrate specificity to the protein networks implicated in neurodegeneration and parkinsonism.

@article{ramirez2006-16964263,
  author  = {Ramirez, A. and Heimbach, A. and Gründemann, J. and Stiller, B. and Hampshire, D. and Cid, L. P. and Goebel, I. and Mubaidin, A. F. and others},
  title   = {{Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase}},
  journal = {Nature genetics},
  year    = {2006},
  doi     = {10.1038/ng1884},
  pmid    = {16964263},
  url     = {https://doi.org/10.1038/ng1884}
}

Key findings

• Our findings link a class of proteins with unknown function and substrate specificity to the protein networks implicated in neurodegeneration and parkinsonism.

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Study details

• Evidence strengthLow

Read the original

• DOI: 10.1038/ng1884
• PubMed: 16964263
• Original source →

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