GM1 ganglioside in Parkinson's disease: Results of a five year open study

Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Journal of the neurological sciences (Impact Factor: 2.47). 03/2010; 292(1-2):45-51. DOI: 10.1016/j.jns.2010.02.009
Source: PubMed


Previous work demonstrated that short-term (i.e., 16 weeks) use of GM1 ganglioside resulted in significant symptom reduction in Parkinson's disease (PD) patients. As GM1 use may have long-term benefit for PD patients, the present study was conducted to evaluate the long-term safety and efficacy of GM1 in PD patients. Twenty-six patients who concluded a previous randomized double blind placebo controlled trial of GM1 volunteered for this open-extension study. At the end of 5 years of GM1 use, patients generally had lower Unified Parkinson's Disease Rating Scale (UPDRS) motor scores (assessed during a practically defined "off" period) than at baseline prior to randomization into the original study. A similar result was found for UPDRS Activities of Daily Living scores. Performance of timed motor tests also remained mostly stable over the 5 year observation period. No consistent clinically significant changes in blood chemistry, hematologic indices or urine chemistry were noted over the course of this study. These results suggest that long-term GM1 use by PD patients is safe and may provide some clinical benefit for PD patients. Additional study is required to more completely assess the degree to which GM1 treatment may be a symptomatic and/or disease-modifying agent for treatment of PD.

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    • "Among gangliosides, GM1 is highly expressed within the brain and is known to be involved in a number of neuronal functions, including neuronal differentiation, survival, neurotransmission and neuritogenesis (Posse de Chaves and Sipione, 2010; Ledeen and Wu, 2015). Interest in GM1 has peaked in recent years for its therapeutic potential in neurodegenerative conditions, namely Huntington's disease (Maglione et al., 2010; Di Pardo et al., 2012) and Parkinson's disease (Schneider et al., 2010). Yet, there is also a substantial body of evidence linking GM1 to the production of amyloid beta fibrils in Alzheimer's disease (Ueno et al., 2014; Yanagisawa, 2015). "
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    ABSTRACT: GM1 ganglioside plays a role in essential neuronal processes, including differentiation, survival, and signaling. Yet, little is known about GM1 species with different sphingosine bases, such as the most abundant species containing 18 carbon atoms in the sphingosine chain (GM1d18:1), and the less abundant containing 20 carbon atoms (GM1d20:1). While absent in the early fetal brain, GM1d20:1 continues to increase throughout pre- and postnatal development and into old age, raising questions about the functional relevance of the GM1d18:1 to GM1d20:1 ratio. Matrix-assisted laser desorption/ionization imaging mass spectrometry is a novel technology that allows differentiation between these two GM1 species and quantification of their expression within an anatomical context. Using this technology, we find GM1d18:1/d20:1 expression ratios are highly specific to defined anatomical brain regions in adult rats. Thus, the ratio was significantly different among different thalamic nuclei and between the corpus callosum and internal capsule. Differential GM1d18:1/GM1d20:1 ratios measured in hippocampal subregions in rat brain complement previous studies conducted in mice. Across layers of the sensory cortex, opposing expression gradients were found for GM1d18:1 and GM1d20:1. Superficial layers demonstrated lower GM1d18:1 and higher GM1d20:1 signal than other layers, while in deep layers GM1d18:1 expression was relatively high and GM1d20:1 expression low. By far the highest GM1d18:1/d20:1 ratio was found in the amygdala. Differential expression of GM1 with d18:1- or d20:1-sphingosine bases in the adult rat brain suggests tight regulation of expression and points toward a distinct functional relevance for each of these GM1 species in neuronal processes.
    Preview · Article · Dec 2015 · Frontiers in Neuroanatomy
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    • "A recent report indicated that chronic GM1 application enhanced RET activity and phosphorylation in the striatum of MPTP-treated mice while promoting recovery of DA and DOPAC deficits (Newburn et al., 2014), consistent with the suggestion that applied GM1 may function as a GDNF mimetic. The experimental paradigm employing exogenous GM1, which may underlie the symptomatic improvements reported in PD clinical trials (Schneider et al., 2010, 2013), does not, in our opinion, reveal the functional role of GM1 in regard to normal GDNF signaling. "
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    ABSTRACT: The new mouse model of PD based on deficiency of GM1 manifests deficient GDNF neuroprotective signaling.•Similar deficiency in GDNF signaling is described in brains of PD subjects, which were also deficient in GM1.•GM1 is necessary for the formation of the GDNF receptor complex; we show that GM1 is an integral part of this complex.•LIGA20, a membrane permeable analog of GM1, rectified the impaired GDNF signaling both in vivo and in vitro.•GM1 in the occipital cortex of PD subjects was significantly below controls (p = 0.002, n = 13/13); systemic effect.
    Full-text · Article · Jan 2015 · Experimental Neurology
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    • "An extensive body of literature can be found on the potential involvement of GM1 gangliosides in the pathogenesis of PD [43], through either accelerated αS aggregation in mice having decreased GM1 levels [44], [45] or a decrease in PD-type symptoms upon administration of GM1 [46], [47]. There is also evidence for a connection between Parkinson’s disease and disorders with defective glucocerebroside metabolism like Gaucher’s disease that indirectly affect GM1 levels [48]. "
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    ABSTRACT: A switch in the conformational properties of α-synuclein (αS) is hypothesized to be a key step in the pathogenic mechanism of Parkinson's disease (PD). Whereas the beta-sheet-rich state of αS has long been associated with its pathological aggregation in PD, a partially alpha-helical state was found to be related to physiological lipid binding; this suggests a potential role of the alpha-helical state in controlling synaptic vesicle cycling and resistance to β-sheet rich aggregation. N-terminal acetylation is the predominant post-translational modification of mammalian αS. Using circular dichroism, isothermal titration calorimetry, and fluorescence spectroscopy, we have analyzed the effects of N-terminal acetylation on the propensity of recombinant human αS to form the two conformational states in interaction with lipid membranes. Small unilamellar vesicles of negatively charged lipids served as model membranes. Consistent with previous NMR studies using phosphatidylserine, we found that membrane-induced α-helical folding was enhanced by N-terminal acetylation and that greater exothermic heat could be measured upon vesicle binding of the modified protein. Interestingly, the folding and lipid binding enhancements with phosphatidylserine in vitro were weak when compared to that of αS with GM1, a lipid enriched in presynaptic membranes. The resultant increase in helical folding propensity of N-acetylated αS enhanced its resistance to aggregation. Our findings demonstrate the significance of the extreme N-terminus for folding nucleation, for relative GM1 specificity of αS-membrane interaction, and for a protective function of N-terminal-acetylation against αS aggregation mediated by GM1.
    Full-text · Article · Jul 2014 · PLoS ONE
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