Objective: To identify potential systemic alterations in CMA and macroautophagy markers, and GBA levels/activity in Peripheral Blood Mononuclear Cells (PBMCs) isolated from PD patients with different genetic backgrounds.

Background: Reduced expression of the lysosomal-associated membrane protein (Lamp)2a and the heat shock cognate (Hsc)70 protein involved in Chaperone-Mediated Autophagy (CMA), and of the lysosomal enzyme glucocerebrosidase (GCase) has been reported in Parkinson’s disease (PD) brains.

Methods: Protein and messenger RNA (mRNA) levels of key lysosomal proteins, total lysosomal and GCase activity were assessed in PBMCs of PD patients from genetically undetermined (GU) background (n=56), alpha-synuclein mutation (G209A/A53T) carriers (n=19), glucocerebrosidase (GBA) mutation carriers (n=14) and age- and sex-matched controls (n=53).

Results: Hsc70 protein levels were reduced in all PD groups, whereas Hsc70 mRNA levels were decreased only in the GU-PD patients. GCase protein levels were reduced only in the A53T-PD and GBA-PD patients, whilst increased GBA mRNA levels and decreased GCase activity was detected only in the GBA-PD patients. No difference was detected in protein and mRNA levels of Lamp2a and macroautophagy markers between PD groups and controls. Lysosomal activity measured only in the GU-PD patients was reduced compared to controls.

Conclusions: Protein levels of Hsc70 are decreased in PBMCs derived from different PD groups, suggestive of an apparent systemic CMA and lysosomal dysfunction. Importantly, GCase protein levels and activity are reduced only in GBA carriers with PD, and thus may serve as a screening tool to identify them, and potentially, as an index of response to PD-modifying therapies.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/lysosomal-alterations-in-peripheral-blood-mononuclear-cells-of-parkinsons-disease-patients/