Neurobiology Group, Biochemical Sciences Division, CSIR-National Chemical Laboratory, Pune, India.
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, India.
J Alzheimers Dis. 2020;75(1):61-71. doi: 10.3233/JAD-191348.
Frontotemporal dementia and parkinsonism-linked to chromosome-17 are a group of diseases with tau mutations leading to primary tauopathies which include progressive supranuclear palsy, corticobasal syndrome, and frontotemporal lobar degeneration. Alzheimer's disease is a non-primary tauopathy, which displays tau neuropathology of excess tangle formation and accumulation. FTDP-17 mutations are responsible for early onset of AD, which can be attributed to compromised physiological functions due to the mutations. Tau is a microtubule-binding protein that secures the integrity of polymerized microtubules in neuronal cells. It malfunctions owing to various insults and stress conditions-like mutations and post-translational modifications.
In this study, we modified the wild type and tau mutants by methyl glyoxal and thus studied whether glycation can enhance the aggregation of predisposed mutant tau.
Tau glycation was studied by fluorescence assays, SDS-PAGE analysis, conformational evaluation, and transmission electron microscopy.
Our study suggests that FTDP-17 mutant P301 L leads to enhanced glycation-induced aggregation as well as advanced glycation end products formation. Glycation forms amorphous aggregates of tau and its mutants without altering its native conformation.
The metabolic anomalies and genetic predisposition have found to accelerate tau-mediated neurodegeneration and prove detrimental for the early-onset of Alzheimer's disease.
额颞叶痴呆和帕金森病相关的 17 号染色体是一组由 tau 突变引起的疾病，导致原发性 tau 病，包括进行性核上性麻痹、皮质基底节综合征和额颞叶痴呆。阿尔茨海默病是非原发性 tau 病，其显示 tau 神经病理学的过度缠结形成和积累。FTDP-17 突变导致早发性 AD，这归因于突变导致的生理功能受损。Tau 是一种微管结合蛋白，可确保神经元细胞中聚合微管的完整性。由于各种损伤和应激条件，如突变和翻译后修饰，它会出现故障。
在这项研究中，我们通过甲基乙二醛修饰野生型和 tau 突变体，从而研究糖基化是否可以增强易感性突变 tau 的聚集。
通过荧光测定法、SDS-PAGE 分析、构象评估和透射电子显微镜研究 tau 糖基化。
我们的研究表明，FTDP-17 突变 P301L 导致增强的糖基化诱导聚集以及晚期糖基化终产物的形成。糖基化形成 tau 及其突变体的无定形聚集物，而不改变其天然构象。
代谢异常和遗传易感性被发现可加速 tau 介导的神经退行性变，并对阿尔茨海默病的早发性产生不利影响。
