Title:Targeting GM2 Ganglioside Accumulation in Dementia: Current Therapeutic Approaches and Future Directions
Volume: 24
Issue: 11
Author(s): Sanjesh Kumar and Siva Prasad Panda*
Affiliation:
- Institute of Pharmaceutical Research, GLA University Mathura, Uttara Pradesh-281406, India
Keywords:
Dementia, GM2 ganglioside, GM2-AP, PKC, synaptic loss, potential therapy.
Abstract: Dementia in neurodegenerative diseases, such as Alzheimer’s disease
(AD), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB) is a
progressive neurological condition affecting millions worldwide. The amphiphilic
molecule GM2 gangliosides are abundant in the human brain and play important roles
in neuronal development, intercellular recognition, myelin stabilization, and signal
transduction. GM2 ganglioside’s degradation requires hexosaminidase A (HexA), a
heterodimer composed of an α subunit encoded by HEXA and a β subunit encoded by
HEXB. The hydrolysis of GM2 also requires a non-enzymatic protein, the GM2
activator protein (GM2-AP), encoded by GM2A. Pathogenic mutations of HEXA,
HEXB, and GM2A are responsible for autosomal recessive diseases known as GM2
gangliosidosis, caused by the excessive intralysosomal accumulation of GM2
gangliosides. In AD, PD and DLB, GM2 ganglioside accumulation is reported to
facilitate Aβ and α-synuclein aggregation into toxic oligomers and plaques through
activation of downstream signaling pathways, such as protein kinase C (PKC) and
oxidative stress factors. This review explored the potential role of GM2 ganglioside
alteration in toxic protein aggregations and its related signaling pathways leading to
neurodegenerative diseases. Further review explored potential therapeutic
approaches, which include synthetic and phytomolecules targeting GM2 ganglioside
accumulation in the brain, holding a promise for providing new and effective
management for dementia.
