Elevated TFEB expression with limited activation in peripheral blood mononuclear cells reflects altered lysosomal...

Lysosomal dysfunction is recognized as a key pathological feature of Parkinson's disease (PD); however, its peripheral signatures remain unclear.

This study evaluated the peripheral profiles of lysosomal hydrolases and their regulation by transcription factor EB (TFEB), focusing on α-galactosidase A (GLA) and β-mannosidase in the peripheral blood mononuclear cells (PBMCs) of 63 PD patients and 44 healthy controls. Lysosomal enzyme activities in PBMC homogenates and serum were quantified using a fluorometric enzymatic assay with kinetic analysis. Protein concentrations were measured by ELISA, and TFEB activation status was evaluated by its phosphorylation level using western blotting.

GLA activity and protein concentrations were higher in the PBMCs of patients, but not for β-mannosidase. TFEB protein concentrations were also elevated and showed positive correlations with lysosomal enzyme protein concentrations. TFEB phosphorylation status showed that the ratio of non-phosphorylated to total TFEB did not differ between PD and controls. However, within the PD group, this ratio negatively correlated with TFEB concentrations, suggesting a potential uncoupling between TFEB expression and its functional activation status. Furthermore, both serum-to-PBMC ratios of GLA activity and protein concentration were lower in PD and were associated with PBMC counts, indicating impaired enzyme release from PBMC.

Elevated TFEB expression in PBMCs may reflect a compensatory response to PD-related cellular stress. However, this response may be functionally insufficient due to limited TFEB activity, potentially leading to reduced lysosomal enzyme release. Thus, peripheral TFEB-related lysosomal abnormalities may serve as indicators of systemic autophagy-lysosome dysregulation in PD.