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

@article{Ramrez2006HereditaryPW,
  title={Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase},
  author={Alfredo Ram{\'i}rez and Andr{\'e} Heimbach and Jan Gr{\"u}ndemann and Barbara Stiller and Daniel J. Hampshire and L. Pablo Cid and Ingrid Goebel and Ammar Fayez Mubaidin and Abdul-Latif Wriekat and Jochen Roeper and A N Al-din and Axel M. Hillmer and Meliha Karsak and Birgit Liss and Christopher Geoffrey Woods and Maria Isabel Behrens and Christian Kubisch},
  journal={Nature Genetics},
  year={2006},
  volume={38},
  pages={1184-1191}
}
Neurodegenerative disorders such as Parkinson and Alzheimer disease cause motor and cognitive dysfunction and belong to a heterogeneous group of common and disabling disorders. [] Key Method 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…
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Update on the genetics of Parkinson's disease
  • T. Gasser
  • Biology
    Movement disorders : official journal of the Movement Disorder Society
  • 2007
TLDR
Evidence is emerging that at least some of these genes may play a direct role in the etiology of the common sporadic form of Parkinson's disease, and the cellular pathways identified in rare monogenic variants of the disease also shed light on the molecular pathogenesis in typical sporadic PD.
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References

SHOWING 1-10 OF 33 REFERENCES
Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1
TLDR
The identification of two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families provide a direct molecular link between mitochondria and the pathogenesis of PD.
Mutations in the parkin gene cause autosomal recessive juvenile parkinsonism
TLDR
Mutations in the newly identified gene appear to be responsible for the pathogenesis of Autosomal recessive juvenile parkinsonism, and the protein product is named ‘Parkin’.
α-Synuclein Is Degraded by Both Autophagy and the Proteasome*
TLDR
It was found that not only is α-synuclein degraded by the proteasome, but it is also degraded by autophagy, which merits consideration as a potential therapeutic for Parkinsons disease, as it is designed for chronic use in humans.
Molecular Pathways of Neurodegeneration in Parkinson's Disease
TLDR
Strategies aimed at restoring complex I activity, reducing oxidative stress and α-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
DJ-1( PARK7), a novel gene for autosomal recessive, early onset parkinsonism
TLDR
Evidence from genetic studies on the yeast DJ-1 homologue, and biochemical studies in murine and human cell lines, suggests a role forDJ-1 as an antioxidant and/or a molecular chaperone, and this will lead to a better understanding of the pathogenesis of DJ- 1-related and common forms of Parkinson’s disease.
Clearance of α-Synuclein Oligomeric Intermediates via the Lysosomal Degradation Pathway
TLDR
It is demonstrated that cells are capable of clearing preformed α-synuclein aggregates via the lysosomal degradation pathway, and it is suggested that enhancing lysOSomal function may be a potential therapeutic strategy to halt or even prevent the pathogenesis of Parkinson's disease and other Lewy body diseases.
Impaired Degradation of Mutant α-Synuclein by Chaperone-Mediated Autophagy
TLDR
It is found that wild-type α-synuclein was selectively translocated into lysosomes for degradation by the chaperone-mediated autophagy pathway, which may underlie the toxic gain-of-function by the A53T and A30P mutants.
Parkinsonism among Gaucher disease carriers
TLDR
Observations indicate that mutant glucocerebrosidase, even in heterozygotes, may be a risk factor for the development of parkinsonism, and will provide insights into the genetics, pathogenesis, and treatment of Parkinson disease.
Kufor Rakeb Disease: Autosomal recessive, levodopa‐responsive parkinsonism with pyramidal degeneration, supranuclear gaze palsy, and dementia
TLDR
Several new features were identified, including facial‐faucial‐finger mini‐myoclonus, visual hallucinations, and oculogyric dystonic spasms inKufor Rakeb disease, and a locus on chromosome 1p36 that was previously assigned PARK9 was identified.
Pallido‐pyramidal degeneration, supranuclear upgaze paresis and dementia: Kufor‐Rakeb syndrome
TLDR
It is suggested that an unusual neurological syndrome in an Arab family with five affected siblings probably represents a new syndrome which is closely related but not identical to the pallido‐pyramidal syndrome.
...
...