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

TY - JOUR

T1 - Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase

AU - Ramirez, Alfredo

AU - Heimbach, André

AU - Gründemann, Jan

AU - Stiller, Barbara

AU - Hampshire, Dan

AU - Cid, L Pablo

AU - Goebel, Ingrid

AU - Mubaidin, Ammar F

AU - Wriekat, Abdul-Latif

AU - Roeper, Jochen

AU - Al-Din, Amir

AU - Hillmer, Axel M

AU - Karsak, Meliha

AU - Liss, Birgit

AU - Woods, C Geoffrey

AU - Behrens, Maria I

AU - Kubisch, Christian

PY - 2006/10

Y1 - 2006/10

N2 - 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.

AB - 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.

KW - Adenosine Triphosphatases/genetics

KW - Dementia/etiology

KW - Endoplasmic Reticulum/enzymology

KW - Female

KW - Humans

KW - Lysosomes/enzymology

KW - Male

KW - Mesencephalon/enzymology

KW - Mutation

KW - Neurons/enzymology

KW - Parkinsonian Disorders/complications

KW - Proton-Translocating ATPases/genetics

U2 - 10.1038/ng1884

DO - 10.1038/ng1884

M3 - SCORING: Journal article

C2 - 16964263

VL - 38

SP - 1184

EP - 1191

JO - NAT GENET

JF - NAT GENET

SN - 1061-4036

IS - 10

ER -