Lee, J.S., Kanai, K., Suzuki, M., Kim, W.S., Yoo, H.S., Fu, Y., Kim, D.K., Jung, B.C., Choi, M., Oh, K.W., Li, Y., Nakatani, M., Nakazato, T., Sekimoto, S., Funayama, M., Yoshino, H., Kubo, S.I., Nishioka, K., Sakai, R., Ueyama, M., Mochizuki, H., Lee, H.J., Sardi, S.P., Halliday, G.M., Nagai, Y., Lee, P.H., Hattori, N., Lee, S.J. (2019). Arylsulfatase A, a genetic modifier of Parkinson's disease, is an α-synuclein chaperone.  Brain 142(9): 2845--2859.

FBrf0245653

Research paper

Mutations in lysosomal genes increase the risk of neurodegenerative diseases, as is the case for Parkinson's disease. Here, we found that pathogenic and protective mutations in arylsulfatase A (ARSA), a gene responsible for metachromatic leukodystrophy, a lysosomal storage disorder, are linked to Parkinson's disease. Plasma ARSA protein levels were changed in Parkinson's disease patients. ARSA deficiency caused increases in α-synuclein aggregation and secretion, and increases in α-synuclein propagation in cells and nematodes. Despite being a lysosomal protein, ARSA directly interacts with α-synuclein in the cytosol. The interaction was more extensive with protective ARSA variant and less with pathogenic ARSA variant than wild-type. ARSA inhibited the in vitro fibrillation of α-synuclein in a dose-dependent manner. Ectopic expression of ARSA reversed the α-synuclein phenotypes in both cell and fly models of synucleinopathy, the effects correlating with the extent of the physical interaction between these molecules. Collectively, these results suggest that ARSA is a genetic modifier of Parkinson's disease pathogenesis, acting as a molecular chaperone for α-synuclein.