1 SCIENTIFIC REPORTS | (2019) 9:8362 | https://doi.org/10.1038/s41598-019-42847-x www.nature.com/scientificreports GM1 Ganglioside Modifes α-Synuclein Toxicity and is Neuroprotective in a Rat α-Synuclein Model of Parkinson’s Disease Jay S. Schneider 1 , Radha Aras 1 , Courtney K. Williams 1 , James B. Koprich 2 , Jonathan M. Brotchie 2 & Vikrant Singh 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 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 defcits. 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 refnement and development of GM1 as a potential disease modifying therapy for PD. 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. Current pharmacotherapies for PD improve many of the motor signs and symptoms of the disease but no drug has yet been identifed that defnitively slows or stops the progression of PD. Disease modifying therapies that can alter clinical progression are sorely needed, however, eforts at fnding such therapies have been limited in part due to uncertainty regarding the pathogenic processes contributing to DA neuron degeneration in PD that should be targeted by a disease modifying therapy. Research from our group 2,3 and others 4,5 suggests that one potential pathogenic mechanism contributing to PD may involve dysregulation of ganglioside synthesis and expression that may contribute to the vulnerability and degeneration of DA neurons in PD. Gangliosides are glycosphingolipids bearing a ceramide anchor, an oligo- saccharide, and one or more sialic acid residues 6 . Te major ganglioside species in brain are GM1, GD1a, GD1b, and GT1b 7 , all contributing to the lipid composition of plasma and intracellular membranes. GM1 and other gangliosides are components of membrane signaling domains called lipid rafs, and in this regard, GM1 contrib- utes to regulating signal transduction for directing neuronal development and cell survival and for modulating a wide variety of cell functions 8 . Further, at least four proteins associated with PD (LRRK2, Parkin, PINK1, and α-synuclein), have been found to associate with lipid rafs and some colocalize with GM1 (along with other raf markers) suggesting that alterations of the GM1-raf association could infuence cellular functions dependent on these proteins 9,10 . In addition to efects exerted at the plasma membrane, GM1 also acts intracellularly where 1 Department of Pathology, Anatomy and Cell Biology, Thomas Jeferson University, Philadelphia, PA, 19107, USA. 2 Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, M5T 2S8, Canada. Correspondence and requests for materials should be addressed to J.S.S. (email: jay.schneider@ jeferson.edu) Received: 26 November 2018 Accepted: 10 April 2019 Published: xx xx xxxx OPEN