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Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson's disease cells.
Neurobiol Dis 2015; 82:235-242ND

Abstract

Heterozygous mutations in GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are a major risk factor for sporadic Parkinson's disease (PD). Defective GCase has been reported in fibroblasts of GBA1-mutant PD patients and pharmacological chaperone ambroxol has been shown to correct such defect. To further explore this issue, we investigated GCase and elements supporting GCase function and trafficking in fibroblasts from sporadic PD patients--with or without heterozygous GBA1 mutations--and healthy subjects, in basal conditions and following in vitro exposure to ambroxol. We assessed protein levels of GCase, lysosomal integral membrane protein-2 (LIMP-2), which mediates GCase trafficking to lysosomes, GCase endogenous activator saposin (Sap) C and parkin, which is involved in degradation of defective GCase. We also measured activities of GCase and cathepsin D, which cleaves Sap C from precursor prosaposin. GCase activity was reduced in fibroblasts from GBA1-mutant patients and ambroxol corrected this defect. Ambroxol increased cathepsin D activity, GCase and Sap C protein levels in all groups, while LIMP-2 levels were increased only in GBA1-mutant PD fibroblasts. Parkin levels were slightly increased only in the PD group without GBA1 mutations and were not significantly modified by ambroxol. Our study confirms that GCase activity is deficient in fibroblasts of GBA1-mutant PD patients and that ambroxol corrects this defect. The drug increased Sap C and LIMP-2 protein levels, without interfering with parkin. These results confirm that chemical chaperone ambroxol modulates lysosomal markers, further highlighting targets that may be exploited for innovative PD therapeutic strategies.

Authors+Show Affiliations

Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Pavia, Italy.Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Pavia, Italy.Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Pavia, Italy.Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Pavia, Italy.Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Pavia, Italy.Center for Research in Neurodegenerative Diseases, C. Mondino National Neurological Institute, Pavia, Italy. Electronic address: fabio.blandini@mondino.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

26094596

Citation

Ambrosi, Giulia, et al. "Ambroxol-induced Rescue of Defective Glucocerebrosidase Is Associated With Increased LIMP-2 and Saposin C Levels in GBA1 Mutant Parkinson's Disease Cells." Neurobiology of Disease, vol. 82, 2015, pp. 235-242.
Ambrosi G, Ghezzi C, Zangaglia R, et al. Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson's disease cells. Neurobiol Dis. 2015;82:235-242.
Ambrosi, G., Ghezzi, C., Zangaglia, R., Levandis, G., Pacchetti, C., & Blandini, F. (2015). Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson's disease cells. Neurobiology of Disease, 82, pp. 235-242. doi:10.1016/j.nbd.2015.06.008.
Ambrosi G, et al. Ambroxol-induced Rescue of Defective Glucocerebrosidase Is Associated With Increased LIMP-2 and Saposin C Levels in GBA1 Mutant Parkinson's Disease Cells. Neurobiol Dis. 2015;82:235-242. PubMed PMID: 26094596.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Ambroxol-induced rescue of defective glucocerebrosidase is associated with increased LIMP-2 and saposin C levels in GBA1 mutant Parkinson's disease cells. AU - Ambrosi,Giulia, AU - Ghezzi,Cristina, AU - Zangaglia,Roberta, AU - Levandis,Giovanna, AU - Pacchetti,Claudio, AU - Blandini,Fabio, Y1 - 2015/06/19/ PY - 2015/03/10/received PY - 2015/06/03/revised PY - 2015/06/15/accepted PY - 2015/6/23/entrez PY - 2015/6/23/pubmed PY - 2016/8/25/medline KW - Fibroblasts KW - Glucocerebrosidase KW - LIMP-2 KW - Lysosomes KW - Parkinson's disease KW - Saposin C SP - 235 EP - 242 JF - Neurobiology of disease JO - Neurobiol. Dis. VL - 82 N2 - Heterozygous mutations in GBA1 gene, encoding for lysosomal enzyme glucocerebrosidase (GCase), are a major risk factor for sporadic Parkinson's disease (PD). Defective GCase has been reported in fibroblasts of GBA1-mutant PD patients and pharmacological chaperone ambroxol has been shown to correct such defect. To further explore this issue, we investigated GCase and elements supporting GCase function and trafficking in fibroblasts from sporadic PD patients--with or without heterozygous GBA1 mutations--and healthy subjects, in basal conditions and following in vitro exposure to ambroxol. We assessed protein levels of GCase, lysosomal integral membrane protein-2 (LIMP-2), which mediates GCase trafficking to lysosomes, GCase endogenous activator saposin (Sap) C and parkin, which is involved in degradation of defective GCase. We also measured activities of GCase and cathepsin D, which cleaves Sap C from precursor prosaposin. GCase activity was reduced in fibroblasts from GBA1-mutant patients and ambroxol corrected this defect. Ambroxol increased cathepsin D activity, GCase and Sap C protein levels in all groups, while LIMP-2 levels were increased only in GBA1-mutant PD fibroblasts. Parkin levels were slightly increased only in the PD group without GBA1 mutations and were not significantly modified by ambroxol. Our study confirms that GCase activity is deficient in fibroblasts of GBA1-mutant PD patients and that ambroxol corrects this defect. The drug increased Sap C and LIMP-2 protein levels, without interfering with parkin. These results confirm that chemical chaperone ambroxol modulates lysosomal markers, further highlighting targets that may be exploited for innovative PD therapeutic strategies. SN - 1095-953X UR - https://www.unboundmedicine.com/medline/citation/26094596/Ambroxol_induced_rescue_of_defective_glucocerebrosidase_is_associated_with_increased_LIMP_2_and_saposin_C_levels_in_GBA1_mutant_Parkinson's_disease_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0969-9961(15)00226-0 DB - PRIME DP - Unbound Medicine ER -