Publication: Saposin C, Key Regulator in the Alpha-Synuclein Degradation Mediated by Lysosome.
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Identifiers
Date
2022-10-05
Authors
Ruz, Clara
Barrero, Francisco J
Pelegrina, Javier
Bandres-Ciga, Sara
Vives, Francisco
Duran, Raquel
Advisors
Journal Title
Journal ISSN
Volume Title
Publisher
MDPI AG
Abstract
Lysosomal dysfunction has been proposed as one of the most important pathogenic molecular mechanisms in Parkinson disease (PD). The most significant evidence lies in the GBA gene, which encodes for the lysosomal enzyme β-glucocerebrosidase (β-GCase), considered the main genetic risk factor for sporadic PD. The loss of β-GCase activity results in the formation of α-synuclein deposits. The present study was aimed to determine the activity of the main lysosomal enzymes and the cofactors Prosaposin (PSAP) and Saposin C in PD and healthy controls, and their contribution to α-synuclein (α-Syn) aggregation. 42 PD patients and 37 age-matched healthy controls were included in the study. We first analyzed the β-GCase, β-galactosidase (β-gal), β-hexosaminidase (Hex B) and Cathepsin D (CatD) activities in white blood cells. We also measured the GBA, β-GAL, β-HEX, CTSD, PSAP, Saposin C and α-Syn protein levels by Western-blot. We found a 20% reduced β-GCase and β-gal activities in PD patients compared to controls. PSAP and Saposin C protein levels were significantly lower in PD patients and correlated with increased levels of α-synuclein. CatD, in contrast, showed significantly increased activity and protein levels in PD patients compared to controls. Increased CTSD protein levels in PD patients correlated, intriguingly, with a higher concentration of α-Syn. Our findings suggest that lysosomal dysfunction in sporadic PD is due, at least in part, to an alteration in Saposin C derived from reduced PSAP levels. That would lead to a significant decrease in the β-GCase activity, resulting in the accumulation of α-syn. The accumulation of monohexosylceramides might act in favor of CTSD activation and, therefore, increase its enzymatic activity. The evaluation of lysosomal activity in the peripheral blood of patients is expected to be a promising approach to investigate pathological mechanisms and novel therapies aimed to restore the lysosomal function in sporadic PD.
Description
MeSH Terms
Cathepsin D
Glucosylceramidase
Hexosaminidase B
Humans
Lysosomes
Mutation
Parkinson Disease
Saposins
alpha-Synuclein
beta-Galactosidase
beta-N-Acetylhexosaminidases
Glucosylceramidase
Hexosaminidase B
Humans
Lysosomes
Mutation
Parkinson Disease
Saposins
alpha-Synuclein
beta-Galactosidase
beta-N-Acetylhexosaminidases
DeCS Terms
Catepsina D
Enfermedad de Parkinson
Glucosilceramidasa
Hexosaminidasa B
Lisosomas
Mutación
Saposinas
alfa-Sinucleína
beta-Galactosidasa
beta-N-Acetilhexosaminidasas
Enfermedad de Parkinson
Glucosilceramidasa
Hexosaminidasa B
Lisosomas
Mutación
Saposinas
alfa-Sinucleína
beta-Galactosidasa
beta-N-Acetilhexosaminidasas
CIE Terms
Keywords
Cathepsin D, PSAP, Parkinson’s disease, lysosomal dysfunction, β-glucocerebrosidase
Citation
Ruz C, Barrero FJ, Pelegrina J, Bandrés-Ciga S, Vives F, Duran R. Saposin C, Key Regulator in the Alpha-Synuclein Degradation Mediated by Lysosome. Int J Mol Sci. 2022 Oct 9;23(19):12004.