Loss of P-type ATPase ATP13A2/PARK9 function induces general lysosomal deficiency and leads to Parkinson disease neurodegeneration

Abstract

Parkinson disease (PD) is a progressive neurodegenerative disorder pathologically characterized by the loss of dopaminergic neurons from the substantia nigra pars compacta and the presence, in affected brain regions, of protein inclusions named Lewy bodies (LBs). The ATP13A2 gene (locus PARK9) encodes the protein ATP13A2, a lysosomal type 5 P-type ATPase that is linked to autosomal recessive familial parkinsonism. The physiological function of ATP13A2, and hence its role in PD, remains to be elucidated. Here, we show that PD-linked mutations in ATP13A2 lead to several lysosomal alterations in ATP13A2 PD patientderived fibroblasts, including impaired lysosomal acidification, decreased proteolytic processing of lysosomal enzymes, reduced degradation of lysosomal substrates, and diminished lysosomal-mediated clearance of autophagosomes. Similar alterations are observed in stable ATP13A2-knockdown dopaminergic cell lines, which are associated with cell death. Restoration of ATP13A2 levels in ATP13A2-mutant/ depleted cells restores lysosomal function and attenuates cell death. Relevant to PD, ATP13A2 levels are decreased in dopaminergic nigral neurons from patients with PD, in which ATP13A2 mostly accumulates within Lewy bodies. Our results unravel an instrumental role of ATP13A2 deficiency on lysosomal function and cell viability and demonstrate the feasibility and therapeutic potential of modulating ATP13A2 levels in the context of PD.autophagy | lysosome | neurodegeneration P arkinson disease (PD) is characterized by extensive cell loss in the substantia nigra pars compacta (SNpc) in conjunction with the formation of intraneuronal proteinaceous cytoplasmic inclusions, named Lewy bodies (LBs) (1). Genetic studies have enabled the identification of 18 gene loci, named PARK1-18, that result in autosomally dominant or recessive inherited forms of PD or are associated with an increased risk for developing PD (2). Among these, the ATP13A2 gene (PARK9) has been linked to autosomal recessive, levodopa-responsive, nigrostriatal-pallidalpyramidal neurodegeneration (Kufor-Rakeb syndrome) as well as to some juvenile and young-onset forms of PD (3-7). The PARK9 gene encodes the protein ATP13A2, a transmembrane lysosomal type 5 P-type ATPase protein consisting of 1,180 amino acid residues (4).Both the cellular function of human ATP13A2 and its role in PD are yet to be elucidated. Genetic studies in yeast suggest that ATP13A2 yeast ortholog is involved in protecting cells against divalent heavy metal cations (8). ATP13A2 has been suggested to protect against α-synuclein misfolding and toxicity in Caenorhabditis elegans and in primary dopaminergic cell cultures (9), suggesting a link between ATP13A2 and α-synuclein pathways. Missense or truncation mutations in ATP13A2 are pathogenic by causing loss of function. For example, cells expressing ATP13A2 mutations exhibit retention of ATP13A2 in the endoplasmic reticulum (ER) and predispose cells to ER stress-induced cell death followed by degradation by means of the ER-associated degr...

A lipid switch unlocks Parkinson’s disease-associated ATP13A2

“…PI(3,5)P2 further controls membrane fusion and fission by activating the mucolipin transient receptor potential channel 1 (27). ATP13A2 might mediate some of the functions of PI(3,5)P2, as loss of ATP13A2 results in an increased lysosomal pH (4) and impaired autophagy (4,5).…”

“…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.…”

Reducing C-terminal truncation mitigates synucleinopathy and neurodegeneration in a transgenic model of multiple system atrophy

“…For Western blot analysis, patches were taken from the motor cortex and striatum of PLP-SYN. Protein extraction and sample preparation was done as previously described (62). A total of 30 μg of protein were loaded and run on 4-15% gradient gels (Bio-Rad Laboratories) to measure oligomeric forms of α-syn using anti-human-specific antibodies Syn-211 (1:1,000, Thermo Fisher Scientific).…”

Autophagosome dynamics in neurodegeneration at a glance

“…Parkinson's-diseaselinked mutations in another gene, ATP13A2 (PARK9) that encode a lysosomal P-type ATPase, also lead to defects in lysosomal acidification, the processing of lysosomal enzymes and the clearance of autophagic substrates (Dehay et al, 2012;Usenovic et al, 2012). Finally, the Parkinson's-diseaseassociated protein LRRK2, which has been implicated in endosomal-lysosomal trafficking, localizes to autophagosomes and activates a Ca 2+ -dependent pathway that leads to increased autophagosome formation and a decreased number of acidic lysosomes (Alegre-Abarrategui et al, 2009;Gómez-Suaga et al, 2012;MacLeod et al, 2013).…”