Disease‐modifying effects of ganglioside GM1 in Huntington's disease models

Abstract

Huntington's disease (HD) is a progressive neurodegenerative disorder characterized by motor, cognitive and psychiatric problems. Previous studies indicated that levels of brain gangliosides are lower than normal in HD models and that administration of exogenous ganglioside GM1 corrects motor dysfunction in the YAC128 mouse model of HD. In this study, we provide evidence that intraventricular administration of GM1 has profound disease‐modifying effects across HD mouse models with different genetic background. GM1 administration results in decreased levels of mutant huntingtin, the protein that causes HD, and in a wide array of beneficial effects that include changes in levels of DARPP32, ferritin, Iba1 and GFAP, modulation of dopamine and serotonin metabolism, and restoration of normal levels of glutamate, GABA, L‐Ser and D‐Ser. Treatment with GM1 slows down neurodegeneration, white matter atrophy and body weight loss in R6/2 mice. Motor functions are significantly improved in R6/2 mice and restored to normal in Q140 mice, including gait abnormalities that are often resistant to treatments. Psychiatric‐like and cognitive dysfunctions are also ameliorated by GM1 administration in Q140 and YAC128 mice. The widespread benefits of GM1 administration, at molecular, cellular and behavioural levels, indicate that this ganglioside has strong therapeutic and disease‐modifying potential in HD.

Intranasal Administration of Mesenchymal Stem Cells Ameliorates the Abnormal Dopamine Transmission System and Inflammatory Reaction in the R6/2 Mouse Model of Huntington Disease

“…Interestingly, our results revealed an increased protein expression level of microglia marker Iba1 in MSC-treated R6/2 mice, indicating an activation of microglia, in contrast to the results of the ameliorated inflammatory modulators. Although it is a common feature that Iba1 expression is increased in both HD patients and symptomatic HD animal models, its expression is decreased in the pre-symptomatic stage of R6/2 mice [74]. Moreover, impaired migration and function of microglia have been reported in YAC128 and BACHD mice in response to brain injury [73].…”

“…Moreover, MSCs secrete various cytokines, trophic and growth factors that support neuronal survival and regeneration [71,72]. Cell migration deficits including impaired function of microglia and the decreased expression of microglia marker Ionized calcium-binding adapter molecule 1 (Iba1) have been observed in HD transgenic mice [73,74]. Besides, the dopaminergic neurotransmission system is also severely impaired [75,76], as shown by the decreased mRNA expressions of both D1 and D2 dopamine receptors and their electrophysiological responses to receptor activation [77].…”

Gangliosides: Treatment Avenues in Neurodegenerative Disease

“…In line with rigorous NIH guidelines, GM1 was tested in three different - and for many aspects complementary—genetic models of HD, i.e., R6/2, Q140, and YAC128 mice (Figure 4) (116–118). Intraventricular infusion of GM1 for 28–42 days (depending on the animal model used) resulted in profound therapeutic and disease-modifying effects across all models (119, 120). Motor behavior was dramatically improved in R6/2 mice and restored to normal in YAC128 and Q140 mice, including gait abnormalities which are often resistant to treatments (119, 120).…”

Anti-inflammatory role of GM1 and modulatory effects of gangliosides on microglia functions

“…is probably the most studied and its neuroprotective properties are well-known [63]. GM1 administration was shown to provide significant benefits in a variety of neurological conditions [38], including stroke [64,65], PD [66,67] and HD [32,41,42]. Some of the underlying mechanisms were neuronal-specific [63,68,69], but whether GM1 could also directly target microglia was not investigated.…”

“…A decrease in ganglioside levels and changes in the relative abundance of specific gangliosides also occur in ageing [28][29][30][31] and in common neurodegenerative conditions, including HD [32,33], PD [34] and AD [35,36]. On the other hand, therapeutic administration of one of the most abundant brain gangliosides, GM1, was shown to provide neuroprotection in models of neuronal injury and neurodegeneration [37][38][39][40] and in genetic models of HD [41,42].…”