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Differential induction of mutant SOD1 misfolding and aggregation by tau and ?-synuclein pathology.

ABSTRACT: BACKGROUND:Prior studies in C. elegans demonstrated that the expression of aggregation-prone polyglutamine proteins in muscle wall cells compromised the folding of co-expressed temperature-sensitive proteins, prompting interest in whether the accumulation of a misfolded protein in pathologic features of human neurodegenerative disease burdens cellular proteostatic machinery in a manner that impairs the folding of other cellular proteins. METHODS:Mice expressing high levels of mutant forms of tau and ?-synuclein (?Syn), which develop inclusion pathologies of the mutant protein in brain and spinal cord, were crossed to mice expressing low levels of mutant superoxide dismutase 1 fused to yellow fluorescent protein (G85R-SOD1:YFP) for aging and neuropathological evaluation. RESULTS:Mice expressing low levels of G85R-SOD1:YFP, alone, lived normal lifespans and were free of evidence of inclusion pathology, setting the stage to use this protein as a reporter of proteostatic function. We observed robust induction of G85R-SOD1:YFP inclusion pathology in the neuropil of spinal cord and brainstem of bigenic mice that co-express high levels of mutant tau in the spinal axis and develop robust spinal tau pathology (JNPL3 mice). In contrast, in crosses of the G85R-SOD1:YFP mice with mice that model spinal ?-synucleinopathy (the M83 model of ?Syn pathology), we observed no G85R-SOD1:YFP inclusion formation. Similarly, in crosses of the G85R-SOD1:YFP mice to mice that model cortical tau pathology (rTg4510 mice), we did not observe induction of G85R-SOD1:YFP inclusions. CONCLUSION:Despite robust burdens of neurodegenerative pathology in M83 and rTg4510 mice, the introduction of the G85R-SOD1:YFP protein was induced to aggregate only in the context of spinal tau pathology present in the JNPL3 model. These findings suggest unexpected specificity, mediated by both the primary protein pathology and cellular context, in the induced "secondary aggregation" of a mutant form of SOD1 that could be viewed as a reporter of proteostatic function.

SUBMITTER: Pace MC

PROVIDER: S-EPMC5960184 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology.

Pace Michael C MC Xu Guilian G Fromholt Susan S Howard John J Giasson Benoit I BI Lewis Jada J Borchelt David R DR

Molecular neurodegeneration 20180518 1

<h4>Background</h4>Prior studies in C. elegans demonstrated that the expression of aggregation-prone polyglutamine proteins in muscle wall cells compromised the folding of co-expressed temperature-sensitive proteins, prompting interest in whether the accumulation of a misfolded protein in pathologic features of human neurodegenerative disease burdens cellular proteostatic machinery in a manner that impairs the folding of other cellular proteins.<h4>Methods</h4>Mice expressing high levels of muta ...[more]

PMID: 29776378

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Project description:RationaleSynucleinopathies, including Parkinson's disease (PD), multiple system atrophy (MSA), and dementia with Lewy bodies (DLB), share a distinct pathological feature, that is, a widespread accumulation of α-synuclein (α-syn) in the brain. There is a significant clinical unmet need for disease-modifying treatments for synucleinopathies. Recently, a seaweed-derived mixture of oligosaccharides sodium oligomannate, GV-971, was approved for Phase 2 clinical trials for PD. This study aimed to further evaluate the therapeutic effects of GV-971 on synucleinopathies using cellular and animal models and explore its associated molecular mechanisms.Methodsα-Syn aggregation was assessed, in vitro and ex vivo, by ThT assay. A dopaminergic neuron cell line, Prnp-SNCAA53T mice, and brain slices from PD and DLB patients were used to determine the efficacy of GV-971 in ameliorating α-syn pathology. Measurements of motor functions, including pole, cylinder, and rotarod tests, were conducted on Prnp-SNCAA53T mice 4 weeks after intragastric administration of GV-971 (200 mg day-1 kg-1 ).ResultsGV-971 effectively prevented α-syn aggregation and even disassembled pre-aggregated α-syn fibrils, in vitro and ex vivo. In addition, GV-971 was able to rescue α-syn-induced neuronal damage and reduced release of extracellular vesicles (EVs), likely via modulating Alix expression. In the Prnp-SNCAA53T mouse model, when treated at the age of 5 months, GV-971 significantly decreased α-syn deposition in the cortex, midbrain, and cerebellum regions, along with ameliorating the motor dysfunctions.ConclusionsOur results indicate that GV-971, when administered at a relatively early stage of the disease process, significantly reduced α-syn accumulation and aggregation in Prnp-SNCAA53T mice. Furthermore, GV-971 corrected α-syn-induced inhibition of EVs release in neurons, contributing to neuronal protection. Future studies are needed to further assess GV-971 as a promising disease-modifying therapy for PD and other synucleinopathies.

Dataset Information

Differential induction of mutant SOD1 misfolding and aggregation by tau and ?-synuclein pathology.

Publications

Differential induction of mutant SOD1 misfolding and aggregation by tau and α-synuclein pathology.

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