Dataset Information

GM1 Ganglioside Modifies α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson's Disease.

ABSTRACT: While GM1 may interact with α-synuclein in vitro to inhibit aggregation, the ability of GM1 to protect against α-synuclein toxicity in vivo has not been investigated. We used targeted adeno-associated viral vector (AAV) overexpression of human mutant α-synuclein (A53T) in the rat substantia nigra (SN) to produce degeneration of SN dopamine neurons, loss of striatal dopamine levels, and behavioral impairment. Some animals received daily GM1 ganglioside administration for 6 weeks, beginning 24 hours after AAV-A53T administration or delayed start GM1 administration for 5 weeks beginning 3 weeks after AAV-A53T administration. Both types of GM1 administration protected against loss of SN dopamine neurons and striatal dopamine levels, reduced α-synuclein aggregation, and delayed start administration of GM1 reversed early appearing behavioral deficits. These results extend prior positive results in MPTP models, are consistent with the results of a small clinical study of GM1 in PD patients that showed slowing of symptom progression with chronic use, and argue for the continued refinement and development of GM1 as a potential disease modifying therapy for PD.

SUBMITTER: Schneider JS

PROVIDER: S-EPMC6557812 | biostudies-other | 2019 Jun

REPOSITORIES: biostudies-other

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GM1 Ganglioside Modifies α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson's Disease.

Schneider Jay S JS Aras Radha R Williams Courtney K CK Koprich James B JB Brotchie Jonathan M JM Singh Vikrant V

Scientific reports 20190610 1

While GM1 may interact with α-synuclein in vitro to inhibit aggregation, the ability of GM1 to protect against α-synuclein toxicity in vivo has not been investigated. We used targeted adeno-associated viral vector (AAV) overexpression of human mutant α-synuclein (A53T) in the rat substantia nigra (SN) to produce degeneration of SN dopamine neurons, loss of striatal dopamine levels, and behavioral impairment. Some animals received daily GM1 ganglioside administration for 6 weeks, beginning 24 hou ...[more]

PMID: 31182727

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Project description:Marketed drugs for Parkinson's disease (PD) treat disease motor symptoms but are ineffective in stopping or slowing disease progression. In the quest of novel pharmacological approaches that may target disease progression, drug-repurposing provides a strategy to accelerate the preclinical and clinical testing of drugs already approved for other medical indications. Here, we targeted the inflammatory component of PD pathology, by testing for the first time the disease-modifying properties of the immunomodulatory imide drug (IMiD) pomalidomide in a translational rat model of PD neuropathology based on the intranigral bilateral infusion of toxic preformed oligomers of human α-synuclein (H-αSynOs). The neuroprotective effect of pomalidomide (20 mg/kg; i.p. three times/week 48 h apart) was tested in the first stage of disease progression by means of a chronic two-month administration, starting 1 month after H-αSynOs infusion, when an already ongoing neuroinflammation is observed. The intracerebral infusion of H-αSynOs induced an impairment in motor and coordination performance that was fully rescued by pomalidomide, as assessed via a battery of motor tests three months after infusion. Moreover, H-αSynOs-infused rats displayed a 40-45% cell loss within the bilateral substantia nigra, as measured by stereological counting of TH + and Nissl-stained neurons, that was largely abolished by pomalidomide. The inflammatory response to H-αSynOs infusion and the pomalidomide treatment was evaluated both in CNS affected areas and peripherally in the serum. A reactive microgliosis, measured as the volume occupied by the microglial marker Iba-1, was present in the substantia nigra three months after H-αSynOs infusion as well as after H-αSynOs plus pomalidomide treatment. However, microglia differed for their phenotype among experimental groups. After H-αSynOs infusion, microglia displayed a proinflammatory profile, producing a large amount of the proinflammatory cytokine TNF-α. In contrast, pomalidomide inhibited the TNF-α overproduction and elevated the anti-inflammatory cytokine IL-10. Moreover, the H-αSynOs infusion induced a systemic inflammation with overproduction of serum proinflammatory cytokines and chemokines, that was largely mitigated by pomalidomide. Results provide evidence of the disease modifying potential of pomalidomide in a neuropathological rodent model of PD and support the repurposing of this drug for clinical testing in PD patients.

Dataset Information

GM1 Ganglioside Modifies α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson's Disease.

Publications

GM1 Ganglioside Modifies α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson's Disease.

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