Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase
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Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. / Ramirez, Alfredo; Heimbach, André; Gründemann, Jan; Stiller, Barbara; Hampshire, Dan; Cid, L Pablo; Goebel, Ingrid; Mubaidin, Ammar F; Wriekat, Abdul-Latif; Roeper, Jochen; Al-Din, Amir; Hillmer, Axel M; Karsak, Meliha; Liss, Birgit; Woods, C Geoffrey; Behrens, Maria I; Kubisch, Christian.
In: NAT GENET, Vol. 38, No. 10, 10.2006, p. 1184-91.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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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 -