Characterization of Lysosomal Protein ATP13A2 in vitro and in vivo

Neurodegenerative diseases are characterized by the progressive death of neurons over time, resulting in motor or cognitive impairment. A spectrum of rare, early-onset neurodegenerative diseases have been causally linked to mutations in the gene ATP13A2, which is most highly expressed in the brain and encodes an endolysosomal P-Type ATPase that transports endocytosed polyamines from the lysosomal lumen to the cytosol. Loss of function of ATP13A2 has been shown to result in lysosomal dysfunction and protein aggregation in neurons and to induce an astrocyte-mediated inflammatory response. Here, we characterized a Danio Rerio model of ATP13A2-associated neurodegeneration by assessing how ATP13A2 deficient zebrafish larvae respond to exogenous polyamines. Survival analysis following treatment with the polyamine spermine indicated that atp13a2 mutant zebrafish are more sensitive to the toxic effects of high concentrations of polyamines than their wild-type counterparts are, and that this sensitivity is accompanied by elevated levels of astrocyte reactivity. We also investigated how ATP13A2 affects the lysosomes of astrocytes, both in basal conditions and in the presence of polyamines. We found that following siRNA knockdown of ATP13A2, there were potential indications of lysosomal enlargement in astrocytes. Together, these findings suggest that ATP13A2’s role as a polyamine transporter can influence astrocyte-mediated neuroinflammation in models of neurodegenerative disease.