Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes

Kong, Stephanie; Chan, Brian K.K.; Park, Jin-Sung; Hill, Kathryn J.; Aitken, Jade B.; Cottle, Louise; Farghaian, Hovik; Cole, Adam R.; Lay, Peter A.; Sue, Carolyn M.; Cooper, Antony A.

doi:10.1093/hmg/ddu099

Cited by 205 publications

(203 citation statements)

References 71 publications

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“…Although we recapitulate the cell-protective effects of ATP13A2 in conditions of Mn 2+ and Zn 2+ toxicity, our biochemical analysis indicates that in contrast to what was suggested in the literature (7)(8)(9)(10)(11)(12), ATP13A2 most likely is not a Mn 2+ or Zn 2+ transporter, as the steady-state levels of autophosphorylated ATP13A2 remain unaffected by Mn 2+ or Zn 2+ .…”

Section: Discussioncontrasting

confidence: 50%

“…This is further supported by the observation that many of the ATP13A2 interacting proteins in human (33) or genetic modifiers of YPK9 in yeast (14) are implicated in vesicular transport. The previously reported effects of ATP13A2 on exosome release (10), Zn 2+ (10)(11)(12) and Mn 2+ (7-9) homeostasis and toxicity, mitochondrial clearance (5), and α-synuclein detoxification (7, 10) might all relate to a role in vesicular transport (14). Based on the phylogenetic relationship with the P4-type ATPases and the lipid effects on autophosphorylation, ATP13A2 may also be a lipid flippase in vesicular pathways (14).…”

Section: Discussionmentioning

confidence: 93%

“…This protective effect of ATP13A2 on α-synuclein toxicity is conserved in yeast, Caenorhabditis elegans, and rat neuronal cells (7). Because ATP13A2 imparts resistance to Mn 2+ (7)(8)(9) and Zn 2+ (10)(11)(12), it was proposed that ATP13A2 may function as a Mn 2+ (7)(8)(9) and/or Zn 2+ transporter (10)(11)(12).…”

mentioning

confidence: 99%

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A lipid switch unlocks Parkinson’s disease-associated ATP13A2

Holemans

Sørensen

Veen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

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ATP13A2 is a lysosomal P-type transport ATPase that has been implicated in Kufor-Rakeb syndrome and Parkinson's disease (PD), providing protection against α-synuclein, Mn 2+ , and Zn 2+ toxicity in various model systems. So far, the molecular function and regulation of ATP13A2 remains undetermined. Here, we demonstrate that ATP13A2 contains a unique N-terminal hydrophobic extension that lies on the cytosolic membrane surface of the lysosome, where it interacts with the lysosomal signaling lipids phosphatidic acid (PA) and phosphatidylinositol(3,5)bisphosphate [PI(3,5)P2]. We further demonstrate that ATP13A2 accumulates in an inactive autophosphorylated state and that PA and PI(3,5)P2 stimulate the autophosphorylation of ATP13A2. In a cellular model of PD, only catalytically active ATP13A2 offers cellular protection against rotenone-induced mitochondrial stress, which relies on the availability of PA and PI(3,5)P2. Thus, the N-terminal binding of PA and PI(3,5)P2 emerges as a key to unlock the activity of ATP13A2, which may offer a therapeutic strategy to activate ATP13A2 and thereby reduce α-synuclein toxicity or mitochondrial stress in PD or related disorders.mitochondria | lysosome | flippase | α-synuclein | P5-type ATPase N euronal fitness depends on optimal lysosomal function and efficient lysosomal delivery of proteins and organelles by autophagy for subsequent breakdown (1, 2). Kufor-Rakeb syndrome (KRS) is an autosomal recessive form of Parkinson's disease (PD) associated with dementia, which is caused by mutations in ATP13A2/PARK9 (3). Mutations in or knockdown (KD) of ATP13A2 lead to lysosomal dysfunctions, including reduced lysosomal acidification, decreased degradation of lysosomal substrates (4), impaired autophagosomal flux (4, 5), and accumulation of fragmented mitochondria (5, 6). By contrast, overexpression (OE) of Ypk9p (i.e., the yeast ATP13A2 ortholog) protects yeast against toxicity of α-synuclein (7), which is the major protein in Lewy bodies, the abnormal protein aggregates that develop inside nerve cells in PD. This protective effect of ATP13A2 on α-synuclein toxicity is conserved in yeast, Caenorhabditis elegans, and rat neuronal cells (7). Because ATP13A2 imparts resistance to Mn 2+ (7-9) and Zn 2+ (10-12), it was proposed that ATP13A2 may function as a Mn 2+ (7-9) and/or Zn 2+ transporter (10-12).ATP13A2 belongs to the P5 subfamily of the P-type ATPase superfamily, which comprises five subfamilies (P1-5) of membrane transporters. P-type ATPases hydrolyze ATP to actively transport inorganic ions across membranes or lipids between membrane leaflets (reviewed in ref. 13). During the transport cycle, a phosphointermediate is formed on a conserved aspartate residue (14). The human P5-type ATPases are divided into two groups, P5A (ATP13A1) and P5B (ATP13A2-5), but their transport specificity has not been established (14-16).P-type ATPases comprise a membrane-embedded core of six transmembrane (TM) helices (M1-6) that form the substrate binding site(s) and entrance/exit pathways for the transp...

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Section: Discussioncontrasting

confidence: 50%

Section: Discussionmentioning

confidence: 93%

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A lipid switch unlocks Parkinson’s disease-associated ATP13A2

Holemans

Sørensen

Veen

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

107

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“…Indeed, in other forms of NCL, Ca 2ϩ and other ion homeostatic disturbances have also been increasingly recognized (51). In particular, Zn 2ϩ homeostasis is a major focus of current research in other forms of NCL and NCL-Parkinsonism overlap disorders, caused by CLN6 mutation and ATP13A2 mutation, respectively (52)(53)(54). In CLN6 disease models, a major disturbance in intracellular Zn 2ϩ regulation and Ca 2ϩ regulation have been identified (55,56).…”

Section: Discussionmentioning

confidence: 99%

Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function

Chandrachud

Walker

Simas

et al. 2015

Journal of Biological Chemistry

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“…ATP13A2 is a poorly understood Type 5 P-type ATPase that appears to localize to lysosomes and/or late endosomes (Kong et al, 2014) and has been implicated in zinc transport (Kong et al, 2014;Tsunemi and Krainc, 2014). A loss-of-function mechanism of disease pathogenesis is suggested by the recessive inheritance pattern and in vitro studies (Park et al, 2011;Podhajska et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

α-Synuclein-Independent Histopathological and Motor Deficits in Mice Lacking the Endolysosomal Parkinsonism Protein Atp13a2

Kett

Stiller

Bernath³

et al. 2015

J. Neurosci.

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Accumulating evidence from genetic and biochemical studies implicates dysfunction of the autophagic-lysosomal pathway as a key feature in the pathogenesis of Parkinson's disease (PD). Most studies have focused on accumulation of neurotoxic ␣-synuclein secondary to defects in autophagy as the cause of neurodegeneration, but abnormalities of the autophagic-lysosomal system likely mediate toxicity through multiple mechanisms. To further explore how endolysosomal dysfunction causes PD-related neurodegeneration, we generated a murine model of Kufor-Rakeb syndrome (KRS), characterized by early-onset Parkinsonism with additional neurological features. KRS is caused by recessive loss-of-function mutations in the ATP13A2 gene encoding the endolysosomal ATPase ATP13A2. We show that loss of ATP13A2 causes a specific protein trafficking defect, and that Atp13a2 null mice develop age-related motor dysfunction that is preceded by neuropathological changes, including gliosis, accumulation of ubiquitinated protein aggregates, lipofuscinosis, and endolysosomal abnormalities. Contrary to predictions from in vitro data, in vivo mouse genetic studies demonstrate that these phenotypes are ␣-synuclein independent. Our findings indicate that endolysosomal dysfunction and abnormalities of ␣-synuclein homeostasis are not synonymous, even in the context of an endolysosomal genetic defect linked to Parkinsonism, and highlight the presence of ␣-synucleinindependent neurotoxicity consequent to endolysosomal dysfunction.

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Parkinson's disease-linked human PARK9/ATP13A2 maintains zinc homeostasis and promotes α-Synuclein externalization via exosomes

Cited by 205 publications

References 71 publications

A lipid switch unlocks Parkinson’s disease-associated ATP13A2

A lipid switch unlocks Parkinson’s disease-associated ATP13A2

Unbiased Cell-based Screening in a Neuronal Cell Model of Batten Disease Highlights an Interaction between Ca2+ Homeostasis, Autophagy, and CLN3 Protein Function

α-Synuclein-Independent Histopathological and Motor Deficits in Mice Lacking the Endolysosomal Parkinsonism Protein Atp13a2

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