Neuronal homeostasis and survival critically depend on an efficient autophagy-lysosomal degradation pathway, especially since neurons cannot reduce the concentration of misfolded
proteins and damaged organelles by cell division. While increasing evidence implicates lysosomal dysfunction in the pathogenesis of
neurodegenerative disorders, the molecular underpinnings of the role of lysosomes in neurodegeneration remain largely unknown. To this end, studies of
neurodegenerative disorders caused by mutations in
lysosomal proteins offer an opportunity to elucidate such mechanisms and potentially identify specific therapeutic targets. One of these disorders is
Kufor-Rakeb syndrome, caused by mutations in the lysosomal
protein ATP13A2/PARK9 and characterized by early-onset
Parkinsonism, pyramidal degeneration and
dementia. We found that loss of ATP13A2 function results in impaired lysosomal function and, consequently, accumulation of SNCA/α-
synuclein and neurotoxicity. Our results suggest that targeting of ATP13A2 to lysosomes to enhance lysosomal function may result in neuroprotection in
Kufor-Rakeb syndrome. From a broader perspective, these findings, together with other recent studies of lysosomal dysfunction in neurodegeneration, suggest that strategies to upregulate lysosomal function in neurons represent a promising therapeutic approach for
neurodegenerative disorders.