Ramirez, A. et al. Hereditary parkinsonism with dementia is caused by mutations in ATP13A2, encoding a lysosomal type 5 P-type ATPase. Nat. Genet. 38, 1184-1191

Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
Nature Genetics (Impact Factor: 29.35). 11/2006; 38(10):1184-91. DOI: 10.1038/ng1884
Source: PubMed


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.

Download full-text


Available from: Maria I Behrens,
    • "The discovery of genes linked to familial forms of PD represents a major advance in PD basic research. These genes include those associated with a-synuclein, parkin, DJ-1, PINK-1, LRRK-2, ATP13A2, PINK-1 (mitochondrial phosphatase and PTEN-induced kinase) gene, and others (Polymeropoulos et al. 1997; Hattori et al. 1998; Abbas et al. 1999; Bonifati et al. 2003b; Valente et al. 2004, Kachergus et al. 2005; Ramirez et al. 2006). The derivative proteins attending these familial forms of PD have additionally advanced our understanding of their roles in PD. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The molecular mechanism responsible for degenerative process in the nigrostriatal dopaminergic system in Parkinson’s disease (PD) remains unknown. One major advance in this field has been the discovery of several genes associated to familial PD, including alpha synuclein, parkin, LRRK2, etc., thereby providing important insight toward basic research approaches. There is an consensus in neurodegenerative research that mitochon dria dysfunction, protein degradation dysfunction, aggregation of alpha synuclein to neurotoxic oligomers, oxidative and endoplasmic reticulum stress, and neuroinflammation are involved in degeneration of the neuromelanin-containing dopaminergic neurons that are lost in the disease. An update of the mechanisms relating to neurotoxins that are used to produce preclinical models of Parkinson´s disease is presented. 6-Hydroxydopamine, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and rotenone have been the most wisely used neurotoxins to delve into mechanisms involved in the loss of dopaminergic neurons containing neuromelanin. Neurotoxins generated from dopamine oxidation during neuromelanin formation are likewise reviewed, as this pathway replicates neurotoxin-induced cellular oxidative stress, inactivation of key proteins related to mitochondria and protein degradation dysfunction, and formation of neurotoxic aggregates of alpha synuclein. This survey of neurotoxin modeling—highlighting newer technologies and implicating a variety of processes and pathways related to mechanisms attending PD—is focused on research studies from 2012 to 2014.
    Neurotoxicity Research 01/2015; 27(3). DOI:10.1007/s12640-015-9519-y · 3.54 Impact Factor
  • Source
    • "Pedigree and cohort studies of patients with inherited forms of PD, which account for only 5–10% of cases [1], have identified numerous genes and loci associated with PD susceptibility [2, 3]. Autosomal recessive mutations in six of these genes have been linked to the disease: Parkin (PARK2) [4], DJ-1 (PARK7) [5], PINK1 (PARK6) [6], ATP13A2 (PARK9) [7], PLA2G6 (PARK14) [8], and FBXO7 (PARK15) [9]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Parkinson's disease (PD) is a major neurodegenerative disorder for which the etiology and pathogenesis remain as elusive as for Alzheimer's disease. PD appears to be caused by genetic and environmental factors, and pedigree and cohort studies have identified numerous susceptibility genes and loci related to PD. Autosomal recessive mutations in the genes Parkin, Pink1, DJ-1, ATP13A2, PLA2G6, and FBXO7 have been linked to PD susceptibility. Such mutations in ATP13A2, also named PARK9, were first identified in 2006 in a Chilean family and are associated with a juvenile-onset, levodopa-responsive type of Parkinsonism called Kufor-Rakeb syndrome (KRS). KRS involves pyramidal degeneration, supranuclear palsy, and cognitive impairment. Here we review current knowledge about the ATP13A2 gene, clinical characteristics of patients with PD-associated ATP13A2 mutations, and models of how the ATP13A2 protein may help prevent neurodegeneration by inhibiting α-synuclein aggregation and supporting normal lysosomal and mitochondrial function. We also discuss another ATP13A2 mutation that is associated with the family of neurodegenerative disorders called neuronal ceroid lipofuscinoses (NCLs), and we propose a single pathway whereby ATP13A2 mutations may contribute to NCLs and Parkinsonism. Finally, we highlight how studies of mutations in this gene may provide new insights into PD pathogenesis and identify potential therapeutic targets.
    BioMed Research International 08/2014; 2014:371256. DOI:10.1155/2014/371256 · 1.58 Impact Factor
  • Source
    • "Notably, two other genes encoding for lysosomal proteins have been linked to PD: the lysosomal type 5 P-type ATPase (ATP13A2—PARK9 locus) (Ramirez et al., 2006) and the enzyme glucocerebrosidase (GBA; Aharon-Peretz et al., 2004; Di Fonzo et al., 2007; Sidransky et al., 2009). While the former has been characterized in rare families with prominent parkinsonism (Ramirez et al., 2006; Di Fonzo et al., 2007), the latter has been identified as risk factor in multicenter genetic analysis of patients (Sidransky et al., 2009). Recently, genetic analysis suggested that lysosomal dysfunction may play an important role in the etiology of DLB (Bras et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurodegenerative diseases are (i) characterized by a selective neuronal vulnerability to degeneration in specific brain regions; and (ii) likely to be caused by disease-specific protein misfolding. Parkinson's disease (PD) is characterized by the presence of intraneuronal proteinacious cytoplasmic inclusions, called Lewy Bodies (LB). α-Synuclein, an aggregation prone protein, has been identified as a major protein component of LB and the causative for autosomal dominant PD. Lysosomes are responsible for the clearance of long-lived proteins, such as α-synuclein, and for the removal of old or damaged organelles, such as mitochondria. Interestingly, PD-linked α-synuclein mutants and dopamine-modified wild-type α-synuclein block its own degradation, which result in insufficient clearance, leading to its aggregation and cell toxicity. Moreover, both lysosomes and lysosomal proteases have been found to be involved in the activation of certain cell death pathways. Interestingly, lysosomal alterations are observed in the brains of patients suffering from sporadic PD and also in toxic and genetic rodent models of PD-related neurodegeneration. All these events have unraveled a causal link between lysosomal impairment, α-synuclein accumulation, and neurotoxicity. In this review, we emphasize the pathophysiological mechanisms connecting α-synuclein and lysosomal dysfunction in neuronal cell death.
    Frontiers in Neuroanatomy 08/2014; 8(83). DOI:10.3389/fnana.2014.00083 · 3.54 Impact Factor
Show more