title: Glucocerebrosidase gene therapy prevents α-synucleinopathy of midbrain dopamine neurons.
abstract: Diminished lysosomal function can lead to abnormal cellular accumulation of specific proteins, including α-synuclein, contributing to disease pathogenesis of vulnerable neurons in Parkinson's disease (PD) and related α-synucleinopathies. GBA1 encodes for the lysosomal hydrolase glucocerebrosidase (GCase), and mutations in GBA1 are a prominent genetic risk factor for PD. Previous studies showed that in sporadic PD, and in normal aging, GCase brain activity is reduced and levels of corresponding glycolipid substrates are increased. The present study tested whether increasing GCase through AAV-GBA1 intra-cerebral gene delivery in two PD rodent models would reduce the accumulation of α-synuclein and protect midbrain dopamine neurons from α-synuclein-mediated neuronal damage. In the first model, transgenic mice overexpressing wildtype α-synuclein throughout the brain (ASO mice) were used, and in the second model, a rat model of selective dopamine neuron degeneration was induced by AAV-A53T mutant α-synuclein. In ASO mice, intra-cerebral AAV-GBA1 injections into several brain regions increased GCase activity and reduced the accumulation of α-synuclein in the substantia nigra and striatum. In rats, co-injection of AAV-GBA1 with AAV-A53T α-synuclein into the substantia nigra prevented α-synuclein-mediated degeneration of nigrostriatal dopamine neurons by 6 months. These neuroprotective effects were associated with altered protein expression of markers of autophagy. These experiments demonstrate, for the first time, the neuroprotective effects of increasing GCase against dopaminergic neuron degeneration, and support the development of therapeutics targeting GCase or other lysosomal genes to improve neuronal handling of α-synuclein.
authors.affiliation: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, MA 02478, USA.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Rocha
authors.affiliation: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, MA 02478, USA.
authors.forename: Gaynor A
authors.initials: GA
authors.lastname: Smith
authors.affiliation: Shire, 300 Shire Way, Lexington, MA 02421, USA.
authors.forename: Eric
authors.initials: E
authors.lastname: Park
authors.affiliation: Shire, 300 Shire Way, Lexington, MA 02421, USA.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Cao
authors.affiliation: Shire, 300 Shire Way, Lexington, MA 02421, USA.
authors.forename: Eilish
authors.initials: E
authors.lastname: Brown
authors.affiliation: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, MA 02478, USA.
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Hayes
authors.affiliation: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, MA 02478, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Beagan
authors.affiliation: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, MA 02478, USA.
authors.forename: Jesse R
authors.initials: JR
authors.lastname: McLean
authors.affiliation: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, MA 02478, USA.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Izen
authors.affiliation: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, MA 02478, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Perez-Torres
authors.affiliation: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, MA 02478, USA. Electronic address: phallett@mclean.harvard.edu.
authors.forename: Penelope J
authors.initials: PJ
authors.lastname: Hallett
authors.affiliation: Neuroregeneration Research Institute, Harvard Medical School/McLean Hospital, Belmont, MA 02478, USA. Electronic address: isacson@hms.harvard.edu.
authors.forename: Ole
authors.initials: O
authors.lastname: Isacson
mesh_terms: D000818:Animals; D000229:Dependovirus / Q000235:genetics; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000201:enzymology* / Q000473:pathology; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D005962:Glucosylceramidase / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000201:enzymology* / Q000473:pathology; D008822:Mice, Transgenic; D019636:Neurodegenerative Diseases / Q000201:enzymology / Q000473:pathology / Q000628:therapy*; D017207:Rats, Sprague-Dawley; D051844:alpha-Synuclein / Q000235:genetics / Q000378:metabolism*
chemical_list: C497604:SNCA protein, human; D051844:alpha-Synuclein; D005962:Glucosylceramidase; D004298:Dopamine
keywords: Autophagy; GBA; Gene therapy; Glucocerebrosidase; Neuroprotection; Parkinson's disease; α-Synuclein