Lipids are in the news again, with a recently published hypothesis proposing that age-dependent decreases in GM1 ganglioside can trigger Parkinson’s disease.(1) Forsayeth and Hadaczek describe parkinsonian-like neurodegeneration in humans and animals with mutations in ganglioside metabolic pathways. In their view, the age-related loss of GM1 prevents glial cell derived neurotrophic factor (GDNF) from signaling and, without this trophic support, selected catecholaminergic neurons die.

Gangliosides are lipids that consist of carbohydrates with a 9-carbon backbone and a carboxylic acid group. They are primarily located in the plasma membranes of nerve cells, where they are involved in cell-cell recognition, adhesion and, importantly for this new hypothesis, signal transduction.(2)  Under physiological conditions, they can form lipid rafts–specialized microdomains in neuronal membranes that help cells perform a host of important functions such as assembly of signaling molecules, concentration of protein receptors, and regulation of intracellular signaling. The graphic above doesn’t show the close association of proteins, carbohydrates, and gangliosides that constitute lipid rafts, but a good graphic can be found in this article.

Forsayeth and Hadaczek describe findings with the B4GALNT1 knockout mouse, which lacks an enzyme involved in the synthesis of GM1 ganglioside. Mice without this enzyme show progressive motor deficits with age, loss of neurons in the substantia nigra, and accumulation of alpha synuclein in the substantia nigra. Administration of LIGA20, a brain-permeable GM1 ganglioside analog, can ameliorate these pathological features.(3)

The proposed mechanism by which reduction or loss of GM1 ganglioside involves GDNF. Forsayeth and Hadaczek believe that locally released GDNF acts in the striatum and possibly other areas to upregulate presynaptic dopaminergic function in response to selected molecular cues. GDNF binding and signaling depends on lipid rafts and, without enough functional GM1 ganglioside, lipid rafts can’t function properly, GDNF cannot exert its trophic effects, and neurons die.(1)

The alpha synuclein accumulation that characterizes Parkinson’s disease is also explained in this hypothesis. Alpha synuclein binds gangliosides, and forms fibrils in the absence of GM1 ganglioside.(4) Alpha synuclein aggregates can be eliminated in the B4GALNT knockout mouse model with overexpression of GDNF in the striatum, which also eliminates the motor deficits shown in this model.(5) The authors suggest that alpha synuclein enables the delivery of GM1 ganglioside to lipid rafts, which are needed for the trophic action of GDNF.

In this hypothesis, the loss of GM1 ganglioside is only one possible route to trophic failure of catecholaminergic neurons and, ultimately, Parkinson’s disease. One can envision other mechanisms that could interfere with GDNF signaling, from reduced release of dense core vesicles (the mechanism proposed by the authors for GDNF release), to GDNF receptor dysfunction, to interference with intracellular signaling mechanisms and pathways. This interesting hypothesis adds to the growing literature implicating lipids in Parkinson’s disease; for a summary of how Parkinson’s disease genes are linked to lipids, see the blog post below left.