Tau mutations
Tau mutations are important factors in the development of neurodegenerative disorders and Alzheimer’s disease (AD). The repeat/interrepeat region of the MAPT gene, which is responsible for coding tau proteins, is where the majority of mutations occur or are located nearby15,20. These mutations cause abnormalities in the function and behavior of tau proteins.
Tau proteins that are transcribed as a result of genetic mutations have a diminished capacity to assemble microtubules in vitro and bind to them to support their assembly15,21–25. In addition, they have a significantly increased tendency to generate aberrant tau fibers. Mutant tau molecules have been proven to cause neuronal death and dementia by blocking tau’s ability to regulate microtubule instability15,24,26–30. In addition, in the brains of transgenic mice that overexpress mutant tau, as well as in the brains of humans with Alzheimer’s disease, mutant tau proteins are found to alter the functioning of nuclear pores involved in nucleocytoplasmic transport, which contributes to neurotoxicity16,31.
Additional effects of mutant tau proteins on microtubule dynamics include a reduction in the average growth rate of microtubules and induction of deformation of the nucleus15,16,32. These altered tau proteins interfere with the role of normal tau in the assembly of tubulin into microtubules and have low microtubule-promoting capabilities33.
Two different hypotheses of molecular mechanisms have been proposed to explain how tau tangles contribute to the etiology of Alzheimer’s disease15. According to the gain-of-toxic function concept, tau mutations are responsible for the production and accumulation of aberrant intracellular tau fibers, which ultimately results in cell death due to the cytotoxic nature of tau fibers15,21,34. On the other hand, the microtubule misregulation concept suggests that tau mutations interfere with the normal capacity of tau to regulate microtubule dynamics, which ultimately leads to cell death15,35–38. This hypothesis was supported by the observation that tau-related diseases are common. The microtubule misregulation paradigm is consistent with research demonstrating the significant role that stringent regulation of microtubule dynamics plays in ensuring the health and survival of cells15,39–43.To create targeted therapeutics to address the underlying causes of Alzheimer’s disease and other neurodegenerative conditions, it is essential to understand the molecular mechanisms underlying tau mutations and the impact of these mutations on cellular function. Ongoing research in this area continues to elucidate the intricacies of tau biology and reveal novel therapeutic intervention pathways.