title: Selective loss of glucocerebrosidase activity in sporadic Parkinson's disease and dementia with Lewy bodies.
abstract: BACKGROUND
  Lysosomal dysfunction is thought to be a prominent feature in the pathogenetic events leading to Parkinson's disease (PD). This view is supported by the evidence that mutations in GBA gene, coding the lysosomal hydrolase β-glucocerebrosidase (GCase), are a common genetic risk factor for PD. Recently, GCase activity has been shown to be decreased in substantia nigra and in cerebrospinal fluid of patients diagnosed with PD or dementia with Lewy Bodies (DLB). Here we measured the activity of GCase and other endo-lysosomal enzymes in different brain regions (frontal cortex, caudate, hippocampus, substantia nigra, cerebellum) from PD (n = 26), DLB (n = 16) and age-matched control (n = 13) subjects, screened for GBA mutations. The relative changes in GCase gene expression in substantia nigra were also quantified by real-time PCR. The role of potential confounders (age, sex and post-mortem delay) was also determined.
  
  
  RESULTS
  Substantia nigra showed a high activity level for almost all the lysosomal enzymes assessed. GCase activity was significantly decreased in the caudate (-23%) and substantia nigra (-12%) of the PD group; the same trend was observed in DLB. In both groups, a decrease in GCase mRNA was documented in substantia nigra. No other lysosomal hydrolase defects were determined.
  
  
  CONCLUSIONS
  The high level of lysosomal enzymes activity observed in substantia nigra, together with the selective reduction of GCase in PD and DLB patients, further support the link between lysosomal dysfunction and PD pathogenesis, favoring the possible role of GCase as biomarker of synucleinopathy. Mapping the lysosomal enzyme activities across different brain areas can further contribute to the understanding of the role of lysosomal derangement in PD and other synucleinopathies.
authors.affiliation: Dipartimento di Medicina, Sezione di Neurologia, Università degli Studi di Perugia, Sant' Andrea delle Fratte, 06132, Perugia, Italy. davide.chiasserini@unipg.it.
authors.forename: Davide
authors.initials: D
authors.lastname: Chiasserini
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123, Perugia, Italy. silvia.paciotti@tiscalinet.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Paciotti
authors.affiliation: Dipartimento di Medicina, Sezione di Neurologia, Università degli Studi di Perugia, Sant' Andrea delle Fratte, 06132, Perugia, Italy. paolo.eusebi@unipg.it.|Health Planning Service, Regional Health Authority of Umbria, 06124, Perugia, Italy. paolo.eusebi@unipg.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Eusebi
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123, Perugia, Italy. persichetti.emanuele@gmail.com.
authors.forename: Emanuele
authors.initials: E
authors.lastname: Persichetti
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123, Perugia, Italy. anna.tasegian@gmail.com.
authors.forename: Anna
authors.initials: A
authors.lastname: Tasegian
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK. marzena.kurzawa2@newcastle.ac.uk.|Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. marzena.kurzawa2@newcastle.ac.uk.
authors.forename: Marzena
authors.initials: M
authors.lastname: Kurzawa-Akanbi
authors.affiliation: Wellcome Centre for Mitochondrial Research, Newcastle University, Newcastle upon Tyne, UK. patrick.chinnery@newcastle.ac.uk.|Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK. patrick.chinnery@newcastle.ac.uk.
authors.forename: Patrick F
authors.initials: PF
authors.lastname: Chinnery
authors.affiliation: Institute of Neuroscience, Medical Toxicology Centre and NIHR Health Protection Research Unit in Chemical and Radiation Threats and Hazards, Wolfson Building, Newcastle University, Claremont Place, Newcastle upon Tyne, NE2 4AA, UK. c.m.morris@newcastle.ac.uk.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Morris
authors.affiliation: Dipartimento di Medicina, Sezione di Neurologia, Università degli Studi di Perugia, Sant' Andrea delle Fratte, 06132, Perugia, Italy. paolo.calabresi@unipg.it.|Fondazione S. Lucia, IRCCS, Rome, Italy. paolo.calabresi@unipg.it.
authors.forename: Paolo
authors.initials: P
authors.lastname: Calabresi
authors.affiliation: Dipartimento di Medicina, Sezione di Neurologia, Università degli Studi di Perugia, Sant' Andrea delle Fratte, 06132, Perugia, Italy. lucilla.parnetti@unipg.it.
authors.forename: Lucilla
authors.initials: L
authors.lastname: Parnetti
authors.affiliation: Department of Pharmaceutical Sciences, University of Perugia, Via Fabretti 48, 06123, Perugia, Italy. tommaso.beccari@unipg.it.
authors.forename: Tommaso
authors.initials: T
authors.lastname: Beccari
mesh_terms: D003704:Dementia / Q000201:enzymology* / Q000235:genetics; D005962:Glucosylceramidase / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D016631:Lewy Bodies / Q000201:enzymology*; D008247:Lysosomes / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010300:Parkinson Disease / Q000201:enzymology* / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D013378:Substantia Nigra / Q000201:enzymology / Q000473:pathology; D051844:alpha-Synuclein / Q000378:metabolism
chemical_list: D051844:alpha-Synuclein; D005962:Glucosylceramidase