Altered Ion Channel Formation by the Parkinson's-Disease-Linked E46K Mutant of α-Synuclein Is Corrected by GM3 but Not by GM1 Gangliosides

Glycosphingolipid Functions

“…Both these proteins were later identified as bona fide GSL binding species (Levy et al 2006). This motif has now been found in asynuclein (Di Pasquale et al 2010), mutated in Parkinson's Disease (PD). aSynuclein binds GM3 (Di Pasquale et al 2010) (and other gangliosides [Schlossmacher et al 2005]) and the binding affinity is increased for the familial mutant form.…”

“…This motif has now been found in asynuclein (Di Pasquale et al 2010), mutated in Parkinson's Disease (PD). aSynuclein binds GM3 (Di Pasquale et al 2010) (and other gangliosides [Schlossmacher et al 2005]) and the binding affinity is increased for the familial mutant form. GM3 binding corrects the ion channel defect of this PD form.…”

Alpha-Synuclein Interactions with Membranes

“…Lipid rafts contain a lot of the ganglioside GM1, and it has been suggested that the gangliosides mediate or facilitate the association of -synuclein with neuronal membranes (Martinez et al, 2007). However, recently Di Pasquale et al identifed a ganglioside-binding domain in -synuclein that showed a marked preference for interactions with GM3, which is a minor brain ganglioside for which the expression increases with age; the Lys 34 and Tyr 39 residues were shown to have critical roles in the GM3 recognition by -synuclein (Di Pasquale et al, 2010).…”

GM1 and GM2 gangliosides: recent developments

“…One hypothesis on the protective role of GM1 is that ganglioside treatment can promote autophagy and clearance of α-synuclein (42), the accumulation of which is associated with Parkinson's disease. By contrast, another study reveals that GM3, rather than GM1, can specifically regulate the permeabilization of the membrane caused by α-synuclein pore formation (43). GM1 has also been used in human clinical trials to treat Parkinson's disease.…”