GM1 Ganglioside and Parkinson’s Disease: History
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Subjects: Biochemistry & Molecular Biology
Contributor:
Robert Ledeen
,
suman chowdhury

GM1 (monosialotetrahexosylganglioside) the "prototype" ganglioside, is a member of the ganglio series of gangliosides which contain one sialic acid residue. GM1 has important physiological properties and impacts neuronal plasticity and repair mechanisms, and the release of neurotrophins in the brain.

  • Parkinson’s disease
  • GM1
  • ganglioside
  • neuroprotection

1. Introduction

The numerous glycosphingolipids that occur in the nervous system and elsewhere are clearly involved in metabolic and pathological changes that accompany Parkinson’s disease [1], but one such molecule, GM1 ganglioside, has received focused attention from several workers for its prominent role in both the etiology and potential treatment of this neurodegenerative condition. GM1 is particularly abundant in neurons and is essential for their complex functioning (see below). The same may be said for ganglioside GD1a, which is identical in structure to GM1 but possesses an additional sialic acid attached to the terminal galactose of GM1[2]. That terminal sialic acid is readily removed by NEU3 neuraminidase, which is situated close to GD1a in the neuronal membrane [3]. This is why GD1a is considered to function as a reserve pool for GM1 as its primary function.

2. GM1 Deficiency Induces Parkinsonism in Mouse PD Model

One of the first clues suggesting that GM1 deficiency constitutes a major risk factor in PD came from the serendipitous observation of mice deficient in GM1 due to biallelic disruption of B4galnt1 (GM2 synthase-B4galnt1–/–) [5]. GM2 is the obligatory precursor to GM1. In addition to motor dysfunction, these mice showed several neuropathologies characteristic of PD, including the key feature of aggregated alpha-synuclein. Additional symptoms included the depletion of striatal dopamine (DA) and loss of DA neurons of the substantia nigra pars compacta (SNpc). Movement disorder was alleviated by L-dopa administration, and neuropathologies were alleviated by LIGA20, an analog of GM1 structurally similar to the latter but is more membrane permeable and, hence, more active. GM1 itself was not effective in those initial studies due to inadequate dosages. 
Study [6] was particularly revealing, in which mice with only monoallelic disruption of the same gene (B4galnt1+/−) manifested Parkinsonian symptoms closely similar to those of the above biallelic mice; such mice had only partial deficiency of GM1. These showed substantially less GM1 in nigral DA neurons than in age-matched controls. Soon after that, the possession of tissues from the occipital cortex of PD patients, and measured their GM1 by the well-established method of high performance thin-layer chromatography (HPTLC) [7]. This too showed a significant deficiency of GM1, even though that part of the brain is not intimately involved in PD pathology.

3. Cause of GM1 Deficiency

It has become recognized that a major part of the GM1 deficiency is due to the aging process itself, consistent with the discovery of Svennerholm and coworkers that both GM1 and GD1a decrease progressively with age . However, that alone would not explain the commonly found difference between PD subjects and age-matched controls, the latter also manifesting age-related decline without developing PD. This points to the existence of one or more additional factors that further depress GM1 and GD1a in PD. One such additional influence could be defective lysosomal hydrolase. That study involved glucocerebrosidase, which is the most prevalent of these, but it is noteworthy that potentially damaging variants of 50 or more less prevalent lysosomal storage disorder genes have been reported in PD cases [8]. Considerable attention has been given to aSyn, the degradation of which is mainly lysosomal, and the malfunction of that process can cause aSyn accumulation and aggregation. Significantly, GM1 was shown to promote autophagy-dependent removal of aSyn in a mouse model of PD .
Moreover, potential influence of the microbiome has to be considered, and it was recently studied in relation to both PD model and PD subjects .
A fairly recent study reported significantly reduced fecal short-chain fatty acids , which were shown to inhibit histone deacetylase [9][10]. Such inhibition promotes epigenetic activation of GM1 synthesis [11][12]. Environmental toxins are also potential inhibitors of GM1 synthesis [13].
Finally, the recent work of Niimi et al. points to enhanced degradation of GM1 as an alternative to impaired synthesis [14][15]. This was based on significant downregulation of glucosylceramide in PD. The higher activity of beta-galactosidase in the blood serum of PD patients was also observed. The proposal of enhanced degradation is worth further consideration.

4. GM1 Decreases in the Periphery as well as Brain

Concerning progressive decline of GM1—due to both age and additional factors—it is important to recognize that this occurs body wide and not only in the brain. Hence, this obviates the need to postulate prion-like movement of aggregated aSyn or to debate body first vs. brain first. Such prion-like movement undoubtedly does occur but likely on a limited scale. It is difficult to observe how this would account for PD manifestations in numerous and diverse locations such as gastrointestinal, cardiovascular, and dermatological neurons among others involved in PD. Since all neurons are dependent on an adequate level of GM1 for viability and neuronal functioning, those in the periphery would be expected to suffer dysfunction—with concomitant PD symptoms—more or less in parallel with those of CNS.
An important and frequently asked question concerns the underlying biochemistry that renders GM1 so essential to neuron function and long-term viability. In general, GM1 serves several essential functions through stereospecific association with particular proteins that preserves the stereospecificity necessary for the normal functioning of those proteins. Well-established examples include nerve growth factor (NGF) and brain-derived growth factor (BDNF), both of which have receptors tightly bound to GM1 for long term preservation of neuronal functioning. 

This entry is adapted from the peer-reviewed paper 10.3390/biom12020173

References

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  2. Ledeen, R.W.; Wu, G. Gangliosides of the Nervous System. In Methods in Molecular Biology; Sonnino, S., Prinetti, A., Eds.; Elsevier: New York, NY, USA, 2018; Volume 1804, pp. 19–25.
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