GM1 Ganglioside Modifies \u03b1-Synuclein Toxicity and is Neuroprotective in a Rat \u03b1-Synuclein Model of Parkinson\u2019s Disease

Jay S Schneider,Courtney K Williams,Jonathan M Brotchie,Radha Aras,Vikrant Singh,James B Koprich

doi:10.1038/s41598-019-42847-x

Jay S Schneider, Courtney K Williams + Show 4 more

Open Access

https://doi.org/10.1038/s41598-019-42847-x

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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.

Highlights

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNc), decreased levels of DA primarily in the caudate nucleus and putamen, accumulation of insoluble α-synuclein aggregates (i.e., Lewy bodies and Lewy neurites)[1], and a slowly progressive worsening of clinical symptoms
Animals that received associated viral vector (AAV)-A53T α-synuclein followed by saline for 6 weeks developed a significant asymmetry in paw use with preference for making contact with the cylinder with ipsilateral forepaw relative to the side of virus injection
The present study demonstrates that GM1 administration is able to exert neuroprotective and potentially neurorestorative effects on the nigrostriatal DA system in a PD model characterized by targeted overexpression of human mutated α-synuclein (A53T) in SNc neurons[29]

Summary

Introduction

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by loss of dopamine (DA)-producing neurons in the substantia nigra pars compacta (SNc), decreased levels of DA primarily in the caudate nucleus and putamen, accumulation of insoluble α-synuclein aggregates (i.e., Lewy bodies and Lewy neurites)[1], and a slowly progressive worsening of clinical symptoms. In addition to effects exerted at the plasma membrane, GM1 acts intracellularly where www.nature.com/scientificreports/ It influences Ca2+ homeostasis, mitochondrial function, and lysosomal integrity, among other processes critical for normal cell function and survival[11,12,13,14]. Several studies have demonstrated PD-relevant and progressive neuropathological (including development of insoluble α-synuclein aggregates) and behavioral features in mice[28], rats[29,30], and non-human primates[31] following SNc-targeted AAV-driven overexpression of human mutant A53T α-synuclein. Using the AAV-A53T α-synuclein rat model, the present study was conducted to investigate the extent to which GM1 ganglioside administration could protect against α-synuclein toxicity and development of PD-relevant pathological changes and behavioral deficits

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