title: Sustained Systemic Glucocerebrosidase Inhibition Induces Brain α-Synuclein Aggregation, Microglia and Complement C1q Activation in Mice.
abstract: OBJECTIVE
  Loss-of-function mutations in GBA1, which cause the autosomal recessive lysosomal storage disease, Gaucher disease (GD), are also a key genetic risk factor for the α-synucleinopathies, including Parkinson's disease (PD) and dementia with Lewy bodies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase and reductions in this enzyme result in the accumulation of the glycolipid substrates glucosylceramide and glucosylsphingosine. Deficits in autophagy and lysosomal degradation pathways likely contribute to the pathological accumulation of α-synuclein in PD. In this report we used conduritol-β-epoxide (CBE), a potent selective irreversible competitive inhibitor of glucocerebrosidase, to model reduced glucocerebrosidase activity in vivo, and tested whether sustained glucocerebrosidase inhibition in mice could induce neuropathological abnormalities including α-synucleinopathy, and neurodegeneration.
  
  
  RESULTS
  Our data demonstrate that daily systemic CBE treatment over 28 days caused accumulation of insoluble α-synuclein aggregates in the substantia nigra, and altered levels of proteins involved in the autophagy lysosomal system. These neuropathological changes were paralleled by widespread neuroinflammation, upregulation of complement C1q, abnormalities in synaptic, axonal transport and cytoskeletal proteins, and neurodegeneration.
  
  
  METHODS
  A reduction in brain GCase activity has been linked to sporadic PD and normal aging, and may contribute to the susceptibility of vulnerable neurons to degeneration. This report demonstrates that systemic reduction of GCase activity using chemical inhibition, leads to neuropathological changes in the brain reminiscent of α-synucleinopathy.
  
  
  CONCLUSIONS
  These data reveal a link between reduced glucocerebrosidase and the development of α-synucleinopathy and pathophysiological abnormalities in mice, and support the development of GCase therapeutics to reduce α-synucleinopathy in PD and related disorders.
authors.affiliation: 1 Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital , Belmont, Massachusetts.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Rocha
authors.affiliation: 1 Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital , Belmont, Massachusetts.
authors.forename: Gaynor A
authors.initials: GA
authors.lastname: Smith
authors.affiliation: 2 Shire , Lexington, Massachusetts.
authors.forename: Eric
authors.initials: E
authors.lastname: Park
authors.affiliation: 2 Shire , Lexington, Massachusetts.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Cao
authors.affiliation: 2 Shire , Lexington, Massachusetts.
authors.forename: Anne-Renee
authors.initials: AR
authors.lastname: Graham
authors.affiliation: 2 Shire , Lexington, Massachusetts.
authors.forename: Eilish
authors.initials: E
authors.lastname: Brown
authors.affiliation: 1 Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital , Belmont, Massachusetts.
authors.forename: Jesse R
authors.initials: JR
authors.lastname: McLean
authors.affiliation: 1 Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital , Belmont, Massachusetts.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Hayes
authors.affiliation: 1 Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital , Belmont, Massachusetts.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beagan
authors.affiliation: 1 Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital , Belmont, Massachusetts.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Izen
authors.affiliation: 1 Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital , Belmont, Massachusetts.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Perez-Torres
authors.affiliation: 1 Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital , Belmont, Massachusetts.
authors.forename: Penelope J
authors.initials: PJ
authors.lastname: Hallett
authors.affiliation: 1 Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital , Belmont, Massachusetts.
authors.forename: Ole
authors.initials: O
authors.lastname: Isacson
mesh_terms: D000818:Animals; D001343:Autophagy; D001370:Axonal Transport; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D003167:Complement Activation; D015922:Complement C1q / Q000378:metabolism*; D005962:Glucosylceramidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007294:Inositol / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D017628:Microglia / Q000502:physiology*; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000201:enzymology; D066263:Protein Aggregation, Pathological / Q000139:chemically induced / Q000201:enzymology*; D011506:Proteins / Q000378:metabolism; D009435:Synaptic Transmission; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: D011506:Proteins; D051844:alpha-Synuclein; C018589:lysosomal proteins; D007294:Inositol; D015922:Complement C1q; D005962:Glucosylceramidase; C011423:conduritol epoxide