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Review
, 23 (4), 314-23

ATP13A2 and Alpha-synuclein: A Metal Taste in Autophagy

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Review

ATP13A2 and Alpha-synuclein: A Metal Taste in Autophagy

Tomás Lopes da Fonseca et al. Exp Neurobiol.

Abstract

Parkinson's Disease (PD) is a complex and multifactorial disorder of both idiopathic and genetic origin. Thus far, more than 20 genes have been linked to familial forms of PD. Two of these genes encode for ATP13A2 and alpha-synuclein (asyn), proteins that seem to be members of a common network in both physiological and disease conditions. Thus, two different hypotheses have emerged supporting a role of ATP13A2 and asyn in metal homeostasis or in autophagy. Interestingly, an appealing theory might combine these two cellular pathways. Here we review the novel findings in the interaction between these two proteins and debate the exciting roads still ahead.

Keywords: ATP13A2; Parkinson's Disease; alpha-synuclein; autophagy; metal homeostasis.

Figures

Fig. 1
Fig. 1
Schematic representation of asyn and ATP13A2. (A) Asyn can be devided in three domains according to its amino acid composition: an N--terminal amphipathic domain where all 6 PD--associated point--mutations are located; a central region known as non--amyloid component (NAC) domain, responsible for the amyloidogenic properties of the protein; and the C--terminal region which is highly acidic. (B) ATP13A2 is an 1180 aa protein with 10 transmembrane domains and four functional domains: catalytic phosphorylation (P1), nucleotide binding (P2 and N) and actuator domain (A).
Fig. 2
Fig. 2
Putative intracellular pathways connecting asyn and ATP13A2. (A) ATP13A2 may be responsible for metal clearance via the lysosome (left side). A failure in this process, caused by mutations or reduced activity of ATP13A2, would lead to the toxic accumulation of metals in the cytoplasm (right side). Furthermore in disease conditions, asyn may increase the intracellular levels of metals, exacerbating cytotoxic effects [55, 60, 62, 64]. (B) Protein and mitochondria degradation by autophagy and mitophagy, respectively, may be critically regulated by ATP13A2 (left side). Upon deficient ATP13A2 activity, accumulation of defective mitochondria or proteins (such as asyn) would contribute to cytotoxicity and disease (right side) [50, 54, 56, 86]. (C1) ATP13A2 may also impact on intracellular Zn2+ homeostasis. Under normal conditions, ATP13A2 may mediate Zn2+ transport across the lysosomal membrane, a process that it thought to influence lysosomal degradation of asyn. On the other hand, under pathological conditions, impaired Zn2+ clearance, caused by defective ATP13A2 activity at the lysosome, can trigger cytoplasmic accumulation and aggregation of asyn [59]. (C2) ATP13A2 may also play a role at the level of multivesicular bodies (MVBs). Thus, functional ATP13A2 might mediate the entrance of Zn2+ into MVB. MVBs may later fuse with autophagosomes containing asyn and be targeted to exocytosis [58].
Fig. 3
Fig. 3
Hypothetical model for the interplay between asyn and ATP13A2. (1) Delivery of Zn2+ to the MVB might be mediated by an ATP13A2/HDAC6 interaction, at the lysosomal membrane. (2) Afterwards, MVBs might engulf cellular contents, including asyn, in a process assisted by molecular chaperones, such as HSP70 (3) The final fate of MVBs (autophagy or exocytosis) might be mediated by these interactions and the cargo (including the proteins and/or organelles) that are being transported.

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