The many faces of ATP13A2 in regulating the pathophysiology of alpha-synuclein

PD is the most common neurodegenerative movement disorder that leads to many motor symptoms such as resting tremor, rigidity, slowness of movement, and postural instability. The incidence of the disease is estimated to double with increased life expectancy in 20 years. One of the hallmarks of PD is the presence of LB in the remaining neurons, which mainly consist of the protein α-synuclein (αsyn). Genetic mutations or multiplications of the SNCA gene were found to be related to an autosomal dominant form of PD. Under the physiological state, there exists a dynamic equilibrium of αsyn between unstructured monomers and different multimers, in the cytosol or associated with the membrane. Imbalance of αsyn synthesis and progressive decline of proteolytic efficiency as well as increased oxidative stress can result in abnormal levels of αsyn, which will favor the formation of oligomers, and eventually accumulate into fibrillar species. ATP13A2 is implicated in a variety of neurodegenerative diseases, including Parkinson's disease and Kufor-Rakeb syndrome, an early-onset atypical Parkinsonism. Loss-of-function mutations in ATP13A2 result in lysosomal deficiency as a consequence of impaired lysosomal export of spermine/spermidine. Besides, accumulating evidence suggests the involvement of ATP13A2 in regulating the fate of αsyn such as cytoplasmic accumulation and external release. However, no consensus has yet been reached on the mechanisms underlying these effects. For this reason, in the first part of the study, we aimed to gain more insight into how ATP13A2 is linked to αsyn in cell models with modified ATP13A2 activity, mainly focusing on its effect on regulating the level of αsyn multimers. We found that loss of ATP13A2 induces αsyn multimerization, which is enhanced in conditions of oxidative stress. In contrast, ATP13A2 WT had a protective effect, which was mediated through the ubiquitin-proteasome system. Interestingly, the catalytically inactive ATP13A2 D508N mutant prevented the upregulation of polyubiquitination and partially contributed to the protection against αsyn multimerization, suggesting a regulatory function independent of the ATPase and transport activity. Spermine was recently found as the substrate of ATP13A2. At high concentration, it exerts toxic effects in neurons and induces αsyn multimerization, which can be prevented by ATP13A2 overexpression. As a lysosomal exporter, ATP13A2 regulates the transmembrane transport of spermine. Deficiency of ATP13A2 function results in increased spermine trapped in the lysosomes and leads to an overall lower polyamine content in cells. We found that loss of ATP13A2 leads to lysosomal membrane leakage, which appears upstream of the impact of ATP13A2 on αsyn multimerization. We also found that ATP13A2 promoted the secretion of αsyn through nanovesicles. In conclusion, our study demonstrates a link between ATP13A2 as a polyamine transporter, lysosomal dysfunction, and αsyn multimerization.

Jaar van publicatie:2022

Toegankelijkheid:Open