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Glucocerebrosidase ( GBA1 ) mutations are the major genetic risk factor for Parkinson’s Disease (PD). The pathogenic mechanism is still unclear, but alterations in lysosomal-autophagy processes are implicated due to reduction of mutated glucocerebrosidase (GCase) in lysosomes. Wild-type GCase activity is also decreased in sporadic PD brains. Small molecule chaperones that increase lysosomal GCase activity have potential to be disease-modifying therapies for  GBA1- associated and sporadic PD. Therefore we have used mouse cortical neurons to explore the effects of the chaperone ambroxol. This chaperone increased wild-type GCase mRNA, protein levels and activity, as well as increasing other lysosomal enzymes and LIMP2, the GCase transporter. Transcription factor EB (TFEB), the master regulator of the CLEAR pathway involved in lysosomal biogenesis was also increased upon ambroxol treatment. Moreover, we found macroautophagy flux blocked and exocytosis increased in neurons treated with ambroxol. We suggest that ambroxol is blocking autophagy and driving cargo towards the secretory pathway. Mitochondria content was also found to be increased by ambroxol via peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α). Our data suggest that ambroxol, besides being a GCase chaperone, also acts on other pathways, such as mitochondria, lysosomal biogenesis, and the secretory pathway.

Effects of ambroxol on the autophagy-lysosome pathway and mitochondria in primary cortical neurons