Kumar Sanjesh, Panda Siva Prasad
Institute of Pharmaceutical Research, GLA University Mathura, Uttara Pradesh-281406, India.
Curr Mol Med. 2024;24(11):1329-1345. doi: 10.2174/0115665240264547231017110613.
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.
神经退行性疾病中的痴呆症，如阿尔茨海默病（AD）、帕金森病（PD）和路易体痴呆（DLB），是一种进行性神经疾病，影响着全球数百万人。两亲性分子GM2神经节苷脂在人脑中含量丰富，在神经元发育、细胞间识别、髓鞘稳定和信号转导中发挥重要作用。GM2神经节苷脂的降解需要己糖胺酶A（HexA），它是一种异二聚体，由HEXA编码的α亚基和HEXB编码的β亚基组成。GM2的水解还需要一种非酶蛋白，即GM2激活蛋白（GM2-AP），由GM2A编码。HEXA、HEXB和GM2A的致病突变导致常染色体隐性疾病，即GM2神经节苷脂贮积症，由GM2神经节苷脂在溶酶体内过度蓄积引起。在AD、PD和DLB中，据报道GM2神经节苷脂的蓄积通过激活下游信号通路，如蛋白激酶C（PKC）和氧化应激因子，促进Aβ和α-突触核蛋白聚集成有毒的寡聚体和斑块。本综述探讨了GM2神经节苷脂改变在有毒蛋白质聚集中的潜在作用及其导致神经退行性疾病的相关信号通路。进一步的综述探讨了潜在的治疗方法，包括针对脑内GM2神经节苷脂蓄积的合成分子和植物分子，有望为痴呆症提供新的有效治疗手段。
