The lysosomal enzyme alpha-Galactosidase A is deficient in Parkinson's disease brain in association with the pathologic accumulation of alpha-synuclein

Abstract

The aberrant accumulation of alpha-synuclein (α-syn) is believed to contribute to the onset and pathogenesis of Parkinson's disease (PD). The autophagy-lysosome pathway (ALP) is responsible for the high capacity clearance of α-syn. ALP dysfunction is documented in PD and pre-clinical evidence suggests that inhibiting the ALP promotes the pathological accumulation of α-syn. We previously identified the pathological accumulation of α-syn in the brains of mice deficient for the soluble lysosomal enzyme alpha-Galactosidase A (α-Gal A), a member of the glycosphingolipid metabolism pathway. In the present study, we quantified α-Gal A activity and levels of its glycosphingolipid metabolites in postmortem temporal cortex specimens from control individuals and in PD individuals staged with respect to α-syn containing Lewy body pathology. In late-state PD temporal cortex we observed significant decreases in α-Gal A activity and the 46kDa "active" species of α-Gal A as determined respectively by fluorometric activity assay and western blot analysis. These decreases in α-Gal A activity/levels correlated significantly with increased α-syn phosphorylated at serine 129 (p129S-α-syn) that was maximal in late-stage PD temporal cortex. Mass spectrometric analysis of 29 different isoforms of globotriaosylceramide (Gb), a substrate of α-Gal A indicated no significant differences with respect to different stages of PD temporal cortex. However, significant correlations were observed between increased levels of several Gb isoforms and with decreased α-Gal A activity and/or increased p129S-α-syn. Deacylated Gb (globotriaosylsphingosine or lyso-Gb) was also analyzed in PD brain tissue but was below the limit of detection of 20pmol/g. Analysis of other lysosomal enzymes revealed a significant decrease in activity for the lysosomal aspartic acid protease cathepsin D but not for glucocerebrosidase (GCase) or cathepsin B in late-stage PD temporal cortex. However, a significant correlation was observed between decreasing GCase activity and increasing p129S-α-syn. Together our findings indicate α-Gal A deficiency in late-stage PD brain that correlates significantly with the pathological accumulation of α-syn, and further suggest the potential for α-Gal A and its glycosphingolipid substrates as putative biomarkers for PD.

Lysosomal Ceramide Metabolism Disorders: Implications in Parkinson’s Disease

“…A study performed in a large cohort composed of n = 648 PD patients and n = 317 controls showed lower blood α-GLA activity associated with PD status [69]. α-GLA activity was also found to be significantly reduced in the temporal cortex of advanced PD patients [70] and in substantia nigra of sporadic PD patients [7]. α-GLA mRNA and protein (particularly the 46 kDa "active" isoform) levels were also reduced in the temporal cortex of these patients.…”

The Vicious Cycle Between α‐Synuclein Aggregation and Autophagic‐Lysosomal Dysfunction

“…Significantly reduced α‐Gal A and CTSD activities were found in temporal cortex of PD patients in advanced stage. The activities of these two enzymes were inversely correlated with levels of p129S–α‐syn and high‐molecular‐weight (hMW) α‐syn species . Of importance, also cathepsin‐B (CTSB) activity correlated negatively with α‐syn hMW species .…”

“…The activities of these two enzymes were inversely correlated with levels of p129S-α-syn and high-molecular-weight (hMW) α-syn species. 65 Of importance, also cathepsin-B (CTSB) activity correlated negatively with α-syn hMW species. 65 In SN and amygdala of sporadic PD patients, HSC70 and LAMP2A were found significantly reduced with respect to both controls and Alzheimer's disease patients.…”

“…65 Of importance, also cathepsin-B (CTSB) activity correlated negatively with α-syn hMW species. 65 In SN and amygdala of sporadic PD patients, HSC70 and LAMP2A were found significantly reduced with respect to both controls and Alzheimer's disease patients. 66 Reduction of LAMP2A protein was also observed in early-stage PD anterior cingulate cortex.…”

Farnesyl Transferase Inhibition for the Treatment of Tauopathies

“…Interventions in upstream pathways such as tau phosphorylation (6) and acetylation inhibitors (7) have shown some efficacy in animal models; however, none of these approaches has had success in human clinical trials. Rapidly growing interest in autophagy as a downstream pathway that mediates tau clearance (8) as well as the implication of autophagy and lysosomes in other neurodegenerative conditions (9)(10)(11) suggests therapeutic opportunities. One potentially druggable pathway linked to autophagy has been suggested in Huntington's disease (HD).…”