ATP13A2 facilitates HDAC6 recruitment to lysosome to promote autophagosome–lysosome fusion

Abstract

Mutations in ATP13A2 cause Kufor-Rakeb syndrome, an autosomal recessive form of juvenile-onset atypical Parkinson’s disease (PD). Recent work tied ATP13A2 to autophagy and other cellular features of neurodegeneration, but how ATP13A2 governs numerous cellular functions in PD pathogenesis is not understood. In this study, the ATP13A2-deficient mouse developed into aging-dependent phenotypes resembling those of autophagy impairment. ATP13A2 deficiency impaired autophagosome–lysosome fusion in cultured cells and in in vitro reconstitution assays. In ATP13A2-deficient cells or Drosophila melanogaster or mouse tissues, lysosomal localization and activity of HDAC6 were reduced, with increased acetylation of tubulin and cortactin. Wild-type HDAC6, but not a deacetylase-inactive mutant, restored autophagosome–lysosome fusion, antagonized cortactin hyperacetylation, and promoted lysosomal localization of cortactin in ATP13A2-deficient cells. Mechanistically, ATP13A2 facilitated recruitment of HDAC6 and cortactin to lysosomes. Cortactin overexpression in cultured cells reversed ATP13A2 deficiency–associated impairment of autophagosome–lysosome fusion. PD-causing ATP13A2 mutants failed to rescue autophagosome–lysosome fusion or to promote degradation of protein aggregates and damaged mitochondria. These results suggest that ATP13A2 recruits HDAC6 to lysosomes to deacetylate cortactin and promotes autophagosome–lysosome fusion and autophagy. This study identifies ATP13A2 as an essential molecular component for normal autophagy flux in vivo and implies potential treatments targeting HDAC6-mediated autophagy for PD.

Whole‐exome sequencing identified compound heterozygous variants in ROR2 gene in a fetus with Robinow syndrome

“…Statistical analysis was performed with Prism 6 software (GraphPad). Two‐tailed Student's t test was used to determine the difference between two groups …”

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease

“…Similarly, cells and Drosophila melanogaster and mouse tissues with loss of ATP13A2, encoded by the PARK9 gene (mutations in which are also related to the early-onset autosomal recessive form of familial PD) exhibit increased acetylation of α-tubulin and cortactin and impaired autophagosome-lysosome fusion, which are associated with reduced lysosomal localization and activity of HDAC6 ( Figure 3 A). In addition, wild-type HDAC6, but not a deacetylase-inactive mutant, antagonizes hyperacetylation and restores autophagosome-lysosome fusion [ 54 ], indicating that reduced activity of HDAC6 deacetylase is an essential pathological factor related to impaired autophagy flux in PD pathogenesis. Activation or overexpression of HDAC6 is thus a potential therapeutic strategy for Parkin- or ATP13A2-related PD.…”

Progress in the molecular pathogenesis and nucleic acid therapeutics for Parkinson's disease in the precision medicine era

“…ATP13A2 controls lysosome homeostasis and regulates autophagosome-lysosome fusion through HDAC6 that is recruited to the lysosome and facilitate autophagy flux. 55 Moreover, ATP13A2 interacts with endocytic signaling lipids through its hydrophobic N-terminal to enable endocytic cargo export. 56 Another PD-related gene product that regulates endosomal-lysosomal trafficking is vacuolar protein sorting protein-associated protein 35 (VPS35, PARK17), a member of the retromer complex.…”

“…73 Other factors such as the accumulation of α-synuclein, ATP13A2 deficiency, and GBA mutations have also been shown to impair mitophagy. [74][75][76] In addition to their bioenergetic functions, mitochondria fine-tune cytosolic Ca 2+ levels by controlling Ca 2+ uptake and efflux through several calcium transporters. 77,78 Mutations in SNCA, PINK1, and LRRK2 have been shown to dysregulate Ca 2+ transporters, resulting in mitochondrial Ca 2+ overload, increased ROS production, and ultimately neuronal cell death.…”