<i>ATP13A2</i>
            missense mutations in juvenile parkinsonism and young onset Parkinson disease

Fonzo, Alessio Di; Chien, Hsin Fen; Socal, Mariana P.; Giraudo, Sabrina; Tassorelli, C.; Iliceto, Gianni; Fabbrini, Giovanni; Marconi, Roberto; Fincati, E.; Abbruzzese, Giovanni; Marini, P.; Squitieri, Ferdinando; Horstink, M.W.I.M.; Montagna, Pasquale; Libera, A. Dalla; Stocchi, Fabrizio; Goldwurm, Stefano; Ferreira, Joaquim J.; Meco, Giuseppe; Martignoni, E.; Lopiano, Leonardo; Jardim, Laura Bannach; Oostra, Ben A.; Barbosa, Egberto Reis; Bonifati, Vincenzo

doi:10.1212/01.wnl.0000260963.08711.08

Cited by 299 publications

(221 citation statements)

References 18 publications

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“…In support of this notion, a role of lysosomal dysfunction in the pathogenesis of PD, it was recently described that ATP13A2, a lysosomal type 5 p-type ATPase, is linked to an autosomal recessive form of early-onset parkinsonism with pyramidal degeneration and dementia: so-called Kufor-Rakeb syndrome (PARK9) (33). It was further shown that several missense mutations of ATP13A2 are associated with some types of juvenile and young onset PD (47). Interestingly, the current study shows that ATP13A2 was co-localized with mutant ␤-syn in lysosomal inclusions formed in cells overexpressing mutant ␤-syn (Fig.…”

Section: Discussionmentioning

confidence: 89%

Enhanced Lysosomal Pathology Caused by β-Synuclein Mutants Linked to Dementia with Lewy Bodies

Wei

Fujita

Nakai

et al. 2007

Journal of Biological Chemistry

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Two missense mutations (P123H and V70M) of ␤-synuclein (␤-syn), the homologue of ␣-syn, have been recently identified in dementia with Lewy bodies. However, the mechanism through which these mutations influence the pathogenesis of dementia with Lewy bodies is unclear. To investigate the role of the ␤-syn mutations in neurodegeneration, each mutant was stably transfected into B103 neuroblastoma cells. Cells overexpressing mutated ␤-syn had eosinophilic cytoplasmic inclusion bodies immunopositive for mutant ␤-syn, and electron microscopy revealed that these cells were abundant in various cytoplasmic membranous inclusions resembling the histopathology of lysosomal storage disease. Consistent with these findings, the inclusion bodies were immunopositive for lysosomal markers, including cathepsin B, LAMP-2, GM2 ganglioside, and ATP13A2, which has recently been linked to PARK9. Notably, formation of these lysosomal inclusions was greatly stimulated by co-expression of ␣-syn, was dependent on the phosphorylation of ␣-syn at Ser-129, and was more efficient with the A53T familial mutant of ␣-syn compared with wild type. Furthermore, the inclusion formation in cells overexpressing mutant ␤-syn and transfected with ␣-syn was significantly suppressed by treatment with autophagy-lysosomal inhibitors, which were associated with impaired clearance of syn proteins and enhanced apoptosis, indicating that formation of lysosomal inclusions might be protective. Collectively, the results demonstrated unambiguously that overexpression of ␤-syn mutants (P123H and V70M) in neuroblastoma cells results in an enhanced lysosomal pathology. We suggest that these missense mutations of ␤-syn might play a causative role in stimulating neurodegeneration.

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Section: Discussionmentioning

confidence: 89%

Enhanced Lysosomal Pathology Caused by β-Synuclein Mutants Linked to Dementia with Lewy Bodies

Wei

Fujita

Nakai

et al. 2007

Journal of Biological Chemistry

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“…A homozygous mutation was also identified in a Japanese patient with clinical features similar to Kufor-Rakeb syndrome but later onset [245]. Mutation screening of PD cases with early onset, but otherwise no atypical signs similar to Kufor-Rakeb syndrome, showed a few other mutations, both homozygous and heterozygous [246,247]. The ATP13A2 protein is a lysosomal ATPase [179], indicating that the lysosomal degradation pathway may play a role in the pathogenesis of PD.…”

Section: Atp13a2 (Park9)mentioning

confidence: 89%

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

et al. 2011

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“…KRS is characterized by juvenile-onset autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration with clinical features of Parkinson disease (PD) plus spasticity, supranuclear upgaze paresis, and dementia (1). Homozygous and heterozygous mutations in ATP13A2 are also found in patients with various parkinsonism, including juvenile parkinsonism, young-onset PD, early-onset PD, and familial PD (2)(3)(4)(5)(6)(7)(8)(9). ATP13A2 encodes a predicted lysosomal P5-type cationtransporting ATPase with multiple transmembrane domains.…”

mentioning

confidence: 99%

Regulation of Intracellular Manganese Homeostasis by Kufor-Rakeb Syndrome-associated ATP13A2 Protein

Tan

Zhang

Jiang

et al. 2011

Journal of Biological Chemistry

131

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Mutations in the ATP13A2 gene are associated with KuforRakeb syndrome (KRS) and are found also in patients with various other types of parkinsonism. ATP13A2 encodes a predicted lysosomal P5-type ATPase that plays important roles in regulating cation homeostasis. Disturbance of cation homeostasis in brains is indicated in Parkinson disease pathogenesis. In this study, we explored the biological function of ATP13A2 as well as the pathogenic mechanism of KRS pathogenic ATP13A2 mutants. The results revealed that wild-type ATP13A2, but not the KRS pathogenic ATP13A2 mutants, protected cells from Mn 2؉ -induced cell death in mammalian cell lines and primary rat neuronal cultures. In addition, wild-type ATP13A2 reduced intracellular manganese concentrations and prevented cytochrome c release from mitochondria compared with the pathogenic mutants. Furthermore, endogenous ATP13A2 was up-regulated upon Mn 2؉ treatment. Our results suggest that ATP13A2 plays important roles in protecting cells against manganese cytotoxicity via regulating intracellular manganese homeostasis. The study provides a potential mechanism of KRS and parkinsonism pathogenesis.Mutations in ATP13A2 were initially identified in patients with Kufor-Rakeb syndrome (KRS), 2 an atypical form of inherited parkinsonism. KRS is characterized by juvenile-onset autosomal recessive nigro-striatal-pallidal-pyramidal neurodegeneration with clinical features of Parkinson disease (PD) plus spasticity, supranuclear upgaze paresis, and dementia (1). Homozygous and heterozygous mutations in ATP13A2 are also found in patients with various parkinsonism, including juvenile parkinsonism, young-onset PD, early-onset PD, and familial PD (2-9). ATP13A2 encodes a predicted lysosomal P5-type cationtransporting ATPase with multiple transmembrane domains. It is highly expressed in the brain, especially in the substantia nigra, the region with characteristic dopaminergic neuronal loss in PD. Ypk9, a yeast ortholog of ATP13A2, was shown to function as a manganese transporter to protect cells from excess Mn 2ϩ exposure, whereas loss of Ypk9 increases the sensitivity of yeast to Mn 2ϩ toxicity (10, 11). Previous studies have suggested that cation disturbance is involved in pathogenesis of PD neurodegeneration. Increased levels of cations, including iron and aluminum, are found in the substantial nigra of the PD patient brain (12, 13). Chronic occupational exposure to copper and/or manganese is associated with higher incidence of PD in a case-control study (14). Furthermore, excess levels of Mn 2ϩ accumulation in brains associated with occupational exposure, psychostimulant drug abuse, and liver disease result in an atypical form of parkinsonism in human (15).PD and parkinsonism are believed to be consequences of interactions between both genetic and environmental components (16,17). In this study, we aimed to explore the connection between the KRS-associated ATP13A2 genetic defect and manganese-associated toxicity. Our results show that wild-type ATP13A2 (ATP13A2WT), but not KRS-as...

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ATP13A2 missense mutations in juvenile parkinsonism and young onset Parkinson disease

Cited by 299 publications

References 18 publications

Enhanced Lysosomal Pathology Caused by β-Synuclein Mutants Linked to Dementia with Lewy Bodies

Enhanced Lysosomal Pathology Caused by β-Synuclein Mutants Linked to Dementia with Lewy Bodies

Epidemiology and etiology of Parkinson’s disease: a review of the evidence

Regulation of Intracellular Manganese Homeostasis by Kufor-Rakeb Syndrome-associated ATP13A2 Protein

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