Lysosomal enzyme activities as possible CSF biomarkers of synucleinopathies

Mutations on the GBA gene, encoding for the lysosomal enzyme beta-glucocerebrosidase (GCase), have been identified as the most common genetic risk factor involved in the development of Parkinson's disease (PD) and dementia with Lewy bodies (DLB), indicating a direct contribution of this enzyme to the pathogenesis of synucleinopathies. Decreased GCase activity has been observed repeatedly in brain tissues and biological fluids of both GBA mutation carrier and non-carrier PD and DLB patients, suggesting that lower GCase activity constitutes a typical feature of these disorders. Additional genetic, pathological and biochemical data on other lysosomal enzymes (e.g., Acid sphingomyelinase, Cathepsin D, alpha-galactosidase A and beta-hexosaminidase) have further strengthened the evidence of a link between lysosomal dysfunction and synucleinopathies. A few studies have been performed for assessing the potential value of lysosomal enzyme activities in cerebrospinal fluid (CSF) as biomarkers for synucleinopathies. The reduction of GCase activity in the CSF of PD and DLB patients was validated in several of them, whereas the behaviour of other lysosomal enzyme activities was not consistently reliable among the studies. More in-depth investigations on larger cohorts, following stringent standard operating procedures should be committed to really understand the diagnostic utility of lysosomal enzymes as biomarkers for synucleinopathies. In this review, we reported the evidences of the association between the defective function of lysosomal proteins and the pathogenesis of synucleinopathies, and examined the role of lysosomal enzyme activities in CSF as reliable biomarkers for the diagnosis of PD and related neurodegenerative disorders.