2. Academic Validation
  3. Glucocerebrosidase Activity Modulates Neuronal Susceptibility to Pathological α-Synuclein Insult

Glucocerebrosidase Activity Modulates Neuronal Susceptibility to Pathological α-Synuclein Insult

  • Neuron. 2020 Mar 4;105(5):822-836.e7. doi: 10.1016/j.neuron.2019.12.004.
Michael X Henderson 1,  Samantha Sedor 2,  Ian McGeary 2,  Eli J Cornblath 3,  Chao Peng 2,  Dawn M Riddle 2,  Howard L Li 2,  Bin Zhang 2,  Hannah J Brown 2,  Modupe F Olufemi 2,  Danielle S Bassett 4,  John Q Trojanowski 2,  Virginia M Y Lee 2
Affiliations

Affiliations

  • 1 Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: [email protected].
  • 2 Institute on Aging and Center for Neurodegenerative Disease Research, Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 3 Department of Bioengineering, School of Engineering & Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
  • 4 Department of Bioengineering, School of Engineering & Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Electrical & Systems Engineering, School of Engineering & Applied Science, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Physics & Astronomy, College of Arts & Sciences, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Psychiatry, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Santa Fe Institute, Santa Fe, NM 87501, USA.
PMID: 31899072 DOI: 10.1016/j.neuron.2019.12.004
Abstract

Mutations in the GBA1 gene are the most common genetic risk factor for Parkinson's disease (PD) and dementia with Lewy bodies (DLB). GBA1 encodes the lysosomal lipid hydrolase glucocerebrosidase (GCase), and its activity has been linked to accumulation of α-synuclein. The current study systematically examines the relationship between GCase activity and both pathogenic and non-pathogenic forms of α-synuclein in primary hippocampal, cortical, and midbrain neuron and astrocyte cultures, as well as in transgenic mice and a non-transgenic mouse model of PD. We find that reduced GCase activity does not result in aggregation of α-synuclein. However, in the context of extant misfolded α-synuclein, GCase activity modulates neuronal susceptibility to pathology. Furthermore, this modulation does not depend on neuron type but rather is driven by the level of pathological α-synuclein seeds. This study has implications for understanding how GBA1 mutations influence PD pathogenesis and provides a platform for testing novel therapeutics.

Keywords

D409V; GBA1; GCase; Lewy body; Parkinson’s disease; glucosylceramide; glucosylsphingosine; network model; neurodegenerative disease; transmission.

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