Lentiviral-mediated knock-down of GD3 synthase protects against MPTP-induced motor deficits and neurodegeneration

Abstract

Converging evidence demonstrates an important role for gangliosides in brain function and neurodegenerative diseases. Exogenous GM1 is broadly neuroprotective, including in rodent, feline, and primate models of Parkinson's disease, and has shown positive effects in clinical trials. We and others have shown that inhibition of the ganglioside biosynthetic enzyme GD3 synthase (GD3S) increases endogenous levels GM1 ganglioside. We recently reported that targeted deletion of St8sia1, the gene that codes for GD3S, prevents motor impairments and significantly attenuates neurodegeneration induced by 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The current study investigated the effects of GD3S inhibition on the neurotoxicity and parkinsonism induced by MPTP. Mice were injected intrastriatally with a lentiviral-vector-mediated shRNA construct targeting GD3S (shGD3S) or a scrambled-sequence control (scrRNA). An MPTP regimen of 18 mg/kg × 5 days reduced tyrosine-hydroxylase-positive neurons in the substantia nigra pars compacta of scrRNA-treated mice by nearly two-thirds. In mice treated with shGD3S the MPTPinduced lesion was approximately half that size. MPTP induced bradykinesia and deficits in fine motor skills in mice treated with scrRNA. These deficits were absent in shGD3S-treated mice. These results suggest that inhibition of GD3S protects against the nigrostriatal damage, bradykinesia, and fine-motor-skill deficits associated with MPTP administration.

Ganglioside GM1 and the Central Nervous System

“…In gene knockout mice, GM1 depletion led to motor disability, neurodegeneration, and other PD symptoms [237,238], which were attenuated by LIGA-20, a GM1 analogue [237]. Similarly, increasing the levels of GM1 was shown to provide protection in both chemically and α-synuclein induced PD animal models [239][240][241][242]. Thus, GM1 plays a mainly protective role against PD-related damages such as dysfunction of excitatory amino acid neurotransmitters, disorder in calcium homeostasis, abnormal metabolism of oxygen free radicals, abnormal trace elements distribution and/or deposition, and excessive apoptosis [243].…”

Gangliosides in the Brain: Physiology, Pathophysiology and Therapeutic Applications

“…On the other hand, experimentally increasing GM1 levels is protective in both chemical and α-synuclein-induced models of PD ( Schneider et al, 1992 , 2019 ; Wei et al, 2009b ; Guo et al, 2020 ). Knock-down or deletion of St8sia1 (GD3 synthase) is also protective in the MPTP model of PD, likely due to accumulation of GM1 that occurs in these models when GM3 cannot be channeled for the synthesis of GD3 ( Figure 1 ; Akkhawattanangkul et al, 2017 ; Dhanushkodi et al, 2019 ).…”

Glycosphingolipid metabolism and its role in ageing and Parkinson’s disease

“…2). A GD3 synthase (St8sia1) (b-series) lentiviral shRNA KO mouse model demonstrated protection against MPTP-induced PD, had increased GM1a (and GD1b) in the brain, and reduced nigrostriatal damage, bradykinesia, and fine-motor-skill deficits [92]. One study which aimed to increase endogenous GM1a, injected Vibrio cholera sialidase in a rodent PD model (MPTP) [93].…”