Neuroinflammation and α-synuclein accumulation in response to glucocerebrosidase deficiency are accompanied by synaptic dysfunction
| Autor: | Sally K.-K. Mak, Novie Ko, Vivian P. Chou, Mary L. LaMarca, Schahram Akbarian, Juliane Karlgren, Steven Samuelsson, Edward I. Ginns, Yin Guo, Arlene Lim, Amy B. Manning-Boğ, Jacqueline Vazquez-DeRose |
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| Rok vydání: | 2014 |
| Předmět: |
Male
medicine.medical_specialty Parkinson's disease Dopamine Endocrinology Diabetes and Metabolism Context (language use) Biology Neurotransmission Synaptic Transmission Biochemistry Mice chemistry.chemical_compound Endocrinology Internal medicine Genetics medicine Animals Humans Molecular Biology Neuroinflammation Inflammation Alpha-synuclein Gaucher Disease Neuronal Plasticity Parkinson Disease Evoked Potentials Motor medicine.disease Corpus Striatum Disease Models Animal MicroRNAs chemistry Mutation Synapses Synaptic plasticity alpha-Synuclein Glucosylceramidase Female Glucocerebrosidase Inositol medicine.drug |
| Zdroj: | Molecular Genetics and Metabolism. 111:152-162 |
| ISSN: | 1096-7192 |
| DOI: | 10.1016/j.ymgme.2013.12.003 |
| Popis: | Clinical, epidemiological and experimental studies confirm a connection between the common degenerative movement disorder Parkinson's disease (PD) that affects over 1 million individuals, and Gaucher disease, the most prevalent lysosomal storage disorder. Recently, human imaging studies have implicated impaired striatal dopaminergic neurotransmission in early PD pathogenesis in the context of Gaucher disease mutations, but the underlying mechanisms have yet to be characterized. In this report we describe and characterize two novel long-lived transgenic mouse models of Gba deficiency, along with a subchronic conduritol-ß-epoxide (CBE) exposure paradigm. All three murine models revealed striking glial activation within nigrostriatal pathways, accompanied by abnormal α-synuclein accumulation. Importantly, the CBE-induced, pharmacological Gaucher mouse model replicated this change in dopamine neurotransmission, revealing a markedly reduced evoked striatal dopamine release (approximately 2-fold) that indicates synaptic dysfunction. Other changes in synaptic plasticity markers, including microRNA profile and a 24.9% reduction in post-synaptic density size, were concomitant with diminished evoked dopamine release following CBE exposure. These studies afford new insights into the mechanisms underlying the Parkinson's-Gaucher disease connection, and into the physiological impact of related abnormal α-synuclein accumulation and neuroinflammation on nigrostriatal dopaminergic neurotransmission. |
| Databáze: | OpenAIRE |
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