Arches. Photo by Daniel Chia
HOPES: Huntington's Outreach Project for Education, at Stanford
Jul
31
2013

Gangliosides

Contrary to what one may think, the brain is the most fat-rich organ in the body.  Aside from being an efficient way to store energy from the food we eat, fat molecules, known as lipids, have many variations in their structure, allowing for a correspondingly large number of additional functions.  For example, some lipids are integral structural components of the membrane that encloses all cells, while others act as hormones that serve as important chemical messengers between different parts of the body.  In the brain and the rest of the central nervous system, lipids play critical roles as signaling molecules that trigger processes such as forming new neuronal connections and promoting brain repair.  Moreover, lipids are a significant component of myelin, the coating around axons that insulates the transmission of electric signals between brain cells just like insulation on electrical wires.  For more information about the role of fats in the nervous system and in HD, click here.

Recently, one family of lipids known as gangliosides has emerged as a potentially important player in HD progression.  Specifically, researchers found lower levels of one type of ganglioside in not only different types of HD mouse models, but also cells isolated from HD patients and postmortem human HD brain samples.  This article describes how gangliosides normally function in the nervous system, how ganglioside function may be disrupted by HD, and how these findings might be useful in the development of a viable HD therapeutic.

Gangliosides and Diseases of the Nervous System^

Gangliosides are a family of lipids first identified in 1942 and so named because they were isolated from ganglion cells of the brain.  Although gangliosides have since been found in cells throughout the body, they are most concentrated in the nervous system, where they seem to exhibit important effects in cell signaling and neuroprotection.  However, their functions are not well understood.

One way of assessing the importance of a molecule in any biological system is by looking at the consequences if the molecule is no longer present.  In the case of gangliosides, many characterized neurological disorders have been linked to defects in ganglioside production.  For example, Guillain-Barré syndrome, an acute inflammatory disease that affects the peripheral nervous system, is caused by the production of antibodies by the immune system that specifically target gangliosides in the body. This type of autoimmune disease, wherein one’s own immune system inadvertently destroys a component of the body, damages the nerve axons that are responsible for nerve signaling and can result in patient paralysis.   Moreover, a genetic mutation that impairs an enzyme important to the production of one type of ganglioside, resulting in complete loss of that ganglioside, leads to a severe infantile-onset epilepsy syndrome characterized by symptoms such as brain atrophy, seizures, and chorea, all of which are symptoms associated with juvenile HD (for more information about juvenile HD, click here).  Since a consequence of the loss of gangliosides is neurodegeneration, gangliosides are thought to play important neuroprotective roles.  In support of this theory, scientists who have genetically engineered mice lacking certain types of gangliosides have found that these mice exhibit severe neurodegeneration and accompanying motor defects that resemble those of HD mouse models.

On the other end of the spectrum, increased levels of gangliosides in nerve cells can result from overproduction of the lipid or problems in its degradation, leading to abnormal buildup.  The genetic disorder Tay-Sachs disease, found mainly in Jewish populations, results from the harmful accumulation of gangliosides in the nerve cells of the brain and other tissues.  Tay-Sachs disease is caused by a genetic mutation that impairs proper degradation of gangliosides. Buildup of the lipid causes nerve cells to become swollen, leading to deterioration of cognitive and motor skills.  Improper control of ganglioside levels has also been observed in cases of Alzheimer’s disease, a neurodegenerative disease characterized by protein aggregates (for more information about Alzheimer’s disease, click here).  Researchers have found that gangliosides bind with amyloid β-protein and facilitate the production of amyloid β-protein aggregates that accumulate in the brains of some Alzheimer’s disease patients.  What is clear is that both the deficiency and excess of gangliosides in the nervous system result in neurodegenerative defects, suggesting that the careful maintenance of ganglioside levels is important for neuronal function.

Gangliosides and HD^

Taking into account the above observations that abnormal ganglioside levels are often implicated in diseases of the nervous system, scientists began to question whether HD may also involve ganglioside irregularities.  It was found in 2010 that the production of GM1, a specific type of ganglioside, appears to be impaired not only in different cell models of HD, but also in cells directly derived from human HD patients.  In this study, Simonetta Sipione and her research group at the University of Alberta first used an in vitro model of HD by growing rat striatal cells that have been engineered to express mutant huntingtin.  By using a protein marker that specifically identifies the GM1 ganglioside, they found that the levels of GM1 in the cells expressing mutant huntingtin were significantly lower compared to normal cells.  More importantly, they observed the same results when they performed the experiment on skin cells isolated directly from human HD patients.  The researchers also found that the levels of an enzyme involved in the production of GM1 were decreased, suggesting that the reason for the lowered levels of GM1 in HD is because of defects in GM1 production.

To determine whether the decreased levels of GM1 have any effects on striatal neuron survival, Sipione’s group of researchers administered GM1 to the cells that express mutant huntingtin.  They found that the recovery of GM1 levels in the cells was accompanied by a drop in the number of cells undergoing apoptosis, or programmed cell death.  On the other hand, when they added a molecule that lowers the amount of GM1 in normal cells, they observed an increase in the number of cells that underwent apoptosis.  These two experiments suggest that GM1 may be an important protective factor in HD – the presence of GM1 may protect cells in the face of stress, but mutant huntingtin leads to decreased levels of GM1.  GM1 deficiency in turn contributes to increased cellular apoptosis that corresponds to neuronal loss in HD.

In a second follow-up study, Sipione’s research group asked whether GM1 could be used as a potential therapeutic in HD mouse models, given the above observations that suggest a potential neuroprotective role.  To answer this question, Sipione used a well-characterized type of HD mouse model that contains a copy of the human mutant huntingtin gene in its genome.  This HD mouse mirrors many of the motor and cognitive symptoms of HD seen in human patients and provides a model of the disease that is useful for testing potential therapeutics (for more information about animal models of HD, click here).  Importantly, these HD mice also exhibited low levels of GM1 compared to wild-type control mice.  The researchers applied therapeutic GM1 by infusing the lipid into the mouse brains. They report that mice already beginning to exhibit HD motor symptoms before the treatment had restored normal motor control in four different test of motor function.  This result is particularly remarkable because the GM1 treatment began following the appearance of symptoms in mice, yet still resulted in complete motor recovery.  Post-symptomatic treatments are important when developing a human therapy because of the difficulties involved in treating an individual carrying the HD mutation throughout their lifetime.

Finally, in light of these encouraging in vitro and in vivo results, the researchers were interested in how GM1 might be causing such a drastic improvement in motor control in HD mice.  The researchers found that GM1 treatment caused a change in the huntingtin protein.  Specifically, they found that GM1-treated brain cells express higher levels of huntingtin protein that has been modified with phosphate tags at two specific amino acid sites within the protein.  Proteins that have been tagged with phosphates, through a process known as phosphorylation, often demonstrate altered activity depending on the specific location of the tag. In the case of the mutant huntingtin protein, studies in mouse models have found that if phosphates are tagged on two specific locations on the huntingtin protein – serine 13 and serine 16 – the toxicity of the mutant huntingtin protein is significantly decreased.  Therefore, the observation that GM1 causes the addition of these phosphate tags at these particular sites of mutant huntingtin raises the possibility that GM1 improves motor control in mice by making the mutant huntingtin protein less harmful to neuronal cells.

Conclusion^

The current research on gangliosides, especially GM1, is very promising for the development of a potential therapeutic for HD, but there remain some challenges.  The current experiments have only tested GM1 treatment in cell and mouse models of HD and the transition into a human study will not necessarily yield results that are as encouraging.  However, ganglioside treatments for other neurological disorders, such as Parkinson’s disease, Alzheimer’s disease, and stroke, have already reached clinical trials.  These studies have met the first criteria of clinical trials by demonstrating that long-term ganglioside treatment does not pose any safety concerns (for more information about clinical trials, click here). While it has yet to be shown if the ganglioside treatments are effective in any of the neurological disorders, these studies, if successful, could pave the way for beginning clinical trials to test the therapeutic value of ganglioside treatment for HD.

Further Reading^

Posse de Chaves E, Sipione S. (2010).  Sphingolipids and gangliosides of the nervous system in membrane function and dysfunction.  FEBS Lett.  584:  1748-1759.

Christie W.  (2013).  Gangliosides:  Structure, Occurence, Biology, and Analysis. AOCS Lipid Library.  http://lipidlibrary.aocs.org/lipids/gang/index.htm.

Yu RK, Ariga T, Yanagisawa M, Zeng G. (2008).  Gangliosides in the nervous system: Biosynthesis and degradation. in Glycoscience (Fraser-Reid, B.; Tatsuka, K.; Thiem, J. ed.) Springer-Verlag. Berlin-Heiderberg, Germany. pp.1671-1695.

Yamashita T, Wu Y-P, Sandhoff R, Werth N, Mizukami H, Ellis JM, Dupree JL, Geyer R, Sandhoff K, Proia RL.  (2005).  Interruption of ganglioside synthesis produces central nervous system degeneration and altered axon-glial interactions.  Proc Natl Acad Sci USA.  102:  2725-2730.

Maglione V, Marchi P, Di Pardo A, Lingrell S, Horkey M, Tidmarsh E, Sipione S. (2010).  Impaired ganglioside metabolism in Huntington’s disease and  neuroprotective role of GM1. J Neurosci.  30: 4072-4080.

Di Pardo A, MaglioneV, Alpaugh M, HorkeyM, Atwal RS, Sassone J, Ciammola A, Steffan JS, Fouad K, Truant R, Sipione S.  (2012). Ganglioside GM1 induces phosphorylation of mutant huntingtin and restores normal motor behavior in Huntington disease mice.  Proc Natl Acad Sci USA.  109: 3528-3533.

Carroll J.  (2012)  Special ‘brain fat’ injection helps HD mice. HDBuzz.  Web:  http://en.hdbuzz.net/072.

-J. Choi, 7-31-13