title: Activation of β-Glucocerebrosidase Reduces Pathological α-Synuclein and Restores Lysosomal Function in Parkinson's Patient Midbrain Neurons.
abstract: Parkinson's disease (PD) is characterized by the accumulation of α-synuclein (α-syn) within Lewy body inclusions in the nervous system. There are currently no disease-modifying therapies capable of reducing α-syn inclusions in PD. Recent data has indicated that loss-of-function mutations in the GBA1 gene that encodes lysosomal β-glucocerebrosidase (GCase) represent an important risk factor for PD, and can lead to α-syn accumulation. Here we use a small-molecule modulator of GCase to determine whether GCase activation within lysosomes can reduce α-syn levels and ameliorate downstream toxicity. Using induced pluripotent stem cell (iPSC)-derived human midbrain dopamine (DA) neurons from synucleinopathy patients with different PD-linked mutations, we find that a non-inhibitory small molecule modulator of GCase specifically enhanced activity within lysosomal compartments. This resulted in reduction of GCase substrates and clearance of pathological α-syn, regardless of the disease causing mutations. Importantly, the reduction of α-syn was sufficient to reverse downstream cellular pathologies induced by α-syn, including perturbations in hydrolase maturation and lysosomal dysfunction. These results indicate that enhancement of a single lysosomal hydrolase, GCase, can effectively reduce α-syn and provide therapeutic benefit in human midbrain neurons. This suggests that GCase activators may prove beneficial as treatments for PD and related synucleinopathies.
  
  
  
  The presence of Lewy body inclusions comprised of fibrillar α-syn within affected regions of PD brain has been firmly documented, however no treatments exist that are capable of clearing Lewy bodies. Here, we used a mechanistic-based approach to examine the effect of GCase activation on α-syn clearance in human midbrain DA models that naturally accumulate α-syn through genetic mutations. Small molecule-mediated activation of GCase was effective at reducing α-syn inclusions in neurons, as well as associated downstream toxicity, demonstrating a therapeutic effect. Our work provides an example of how human iPSC-derived midbrain models could be used for testing potential treatments for neurodegenerative disorders, and identifies GCase as a critical therapeutic convergence point for a wide range of synucleinopathies.
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, Massachusetts 02129, The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago IL 60611, krainc@northwestern.edu jmazzulli@northwestern.edu.
authors.forename: Joseph R
authors.initials: JR
authors.lastname: Mazzulli
authors.affiliation: The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago IL 60611.
authors.forename: Friederike
authors.initials: F
authors.lastname: Zunke
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, Massachusetts 02129, The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago IL 60611.
authors.forename: Taiji
authors.identifier: 0000-0002-0021-0708
authors.initials: T
authors.lastname: Tsunemi
authors.affiliation: The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago IL 60611.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Toker
authors.affiliation: The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago IL 60611.
authors.forename: Sohee
authors.initials: S
authors.lastname: Jeon
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, Massachusetts 02129, The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago IL 60611.
authors.forename: Lena F
authors.initials: LF
authors.lastname: Burbulla
authors.affiliation: Department of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, 20850.
authors.forename: Samarjit
authors.initials: S
authors.lastname: Patnaik
authors.affiliation: Section of Molecular Neurogenetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland, 20892, and.
authors.forename: Ellen
authors.identifier: 0000-0002-3019-8500
authors.initials: E
authors.lastname: Sidransky
authors.affiliation: Department of Preclinical Innovation, National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, Maryland, 20850.
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Marugan
authors.affiliation: Department of Neurogenetics, Kolling Institute of Medical Research, Royal North Shore Hospital and the University of Sydney, St Leonards, New South Wales 2065, Australia.
authors.forename: Carolyn M
authors.initials: CM
authors.lastname: Sue
authors.affiliation: Department of Neurology, Massachusetts General Hospital, Harvard Medical School, MassGeneral Institute for Neurodegeneration, Charlestown, Massachusetts 02129, The Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago IL 60611, krainc@northwestern.edu jmazzulli@northwestern.edu.
authors.forename: Dimitri
authors.initials: D
authors.lastname: Krainc
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005962:Glucosylceramidase / Q000378:metabolism*; D006801:Humans; D057026:Induced Pluripotent Stem Cells; D052119:Lysosomal-Associated Membrane Protein 2 / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D008636:Mesencephalon / Q000473:pathology*; D009154:Mutation / Q000235:genetics; D009447:Neuroblastoma / Q000473:pathology; D019636:Neurodegenerative Diseases / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D010300:Parkinson Disease / Q000473:pathology*; D006180:Proton-Translocating ATPases / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism / Q000473:pathology; D016708:Synaptophysin / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
chemical_list: C514983:ATP13A2 protein, human; D004791:Enzyme Inhibitors; D052119:Lysosomal-Associated Membrane Protein 2; C497604:SNCA protein, human; D016708:Synaptophysin; D051844:alpha-Synuclein; D005962:Glucosylceramidase; D006180:Proton-Translocating ATPases
keywords: Parkinson's disease; glucocerebrosidase; induced pluripotent stem cells; lysosomes; synucleinopathy; α-synuclein