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.