**6. CSF lysosomal enzyme activities as possible marker of synucleinopathies**

Recently it became evident that accumulation of unwanted and misfolded protein play a central role in the PD pathogenesis. An involvement of the lysosomal system has been postulated. Lysosomal activity decreased over the lifespan and a lysosomal malfunction has been linked with cronic neurodegenerative disorders (Terman, 2006; Pan et al., 2008). This assumption has been confirmed by the selective inhibition of lysosomal enzyme in different cellular models that leads to protein aggregation, synaptic loss and neuronal death (Felbor et al., 2002; Bendiske & Bahr, 2003). Furthermore, in experimental system, has been noted that α-synuclein aggregation leads to inhibition of lysosomal functions, triggering a vicious cycle (Bennett et al., 2005; Cuervo et al., 2004). On the basis of these evidences was performed a comparative analysis of the activity of β−glucocerebrosidase (EC 3.2.1.45), αmannosidase (EC 3.2.1.24), β-mannosidase (EC 3.2.1.25), β-hexosaminidase (EC 3.2.1.52) and β-galactosidase (EC 3.2.1.23) in cerebrospinal fluid (CSF) of Parkinson's disease (PD) subjects and age matched controls first (Balducci et al., 2007), and then in Dementia with Lewy bodies (DLB), Alzheimer's disease (AD) and Frontotemporal Dementia (FTD) patients as well as in age matched controls (Parnetti et al., 2009). The framekork is different in the different neurodegenerative diseases, in PD patients a reduced activity of βglucocerebrosidase, β-mannosidase and α-mannosidase was found, whereas βgalactosidase and β-hexosaminidase remain unchanged. In DLB patients, all the enzymes tested showed a decrease activity with β−glucocerebrosidase with the lower value. In FTD patients, only α-mannosidase activity was lower than controls, while the other enzymes showed unchanged acticities. α-mannosidase and β-hexosaminidase are the only two enzyme that showed reduced activity in AD patients.

The data suggest a significant involvement of the ensosomal-lysosomal system in the neurodegenerative diseases examined. Moreover, the different pattern of lysosomal activity can reflect the diverse implication of the lysosomal apparatous in the distinct neurodegenerative pathologies. It has also been hypotized that ameliorate the activity of the lysosomal system can be a possible therapeutic strategy for these disorders characterized by misfolding and aggregation of wild-type or mutant protein in the cytoplas of neuronal cells (Lee et al., 2004).
