Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey

Abstract

Tau proteins are known to be mainly involved in regulation of microtubule dynamics. Besides this function, which is critical for axonal transport and signal transduction, tau proteins also have other roles in neurons. Moreover, tau proteins are turned into aggregates and consequently trigger many neurodegenerative diseases termed tauopathies, of which Alzheimer’s disease (AD) is the figurehead. Such pathological aggregation processes are critical for the onset of these diseases. Among the various causes of tau protein pathogenicity, abnormal tau mRNA metabolism, expression and dysregulation of tau post-translational modifications are critical steps. Moreover, the relevance of tau function to general mRNA metabolism has been highlighted recently in tauopathies. In this review, we mainly focus on how mRNA metabolism impacts the onset and development of tauopathies. Thus, we intend to portray how mRNA metabolism of, or mediated by, tau is associated with neurodegenerative diseases.

Tau Isoforms: Gaining Insight into MAPT Alternative Splicing

“…NTR is also called “Projection domain”, as it projects away from the microtubule to interact with other cytoskeletal and cytoplasmic proteins or organelles, such as annexins, synaptic vesicle-associated proteins, or mitochondria [ 26 , 68 , 69 ]. NTR may regulate the subcellular distribution of Tau into axons and may also have a role in signaling and Tau aggregation [ 62 , 70 , 71 ]. Tau has been demonstrated to bind to DNA and RNA, as well as interact with chromatin and within the inner side of the nuclear lamina.…”

“…This region interacts with many kinases and phosphatases and seems to be involved in the regulation of Tau phosphorylation and in promoting microtubule assembly and stability with MTBD. The PRR is also involved in interactions with proteins containing a Src homology-3 (SH3) domain, playing an important role in protein folding [ 68 , 71 , 72 , 73 ]. Gene-ontology analysis revealed that the group of proteins that specifically interact with the PRR showed a remarkable enrichment of proteins involved in cell signaling mechanisms [ 68 ].…”

“…Being positively charged, the MTBD can also easily make electrostatic interactions with the negatively charged C-terminal region, which seems to be essential for the extremely dynamic “kiss-and-hop” interaction (rapid binding and detaching from the microtubule surface, with a mean dwell time of single Tau molecules in the millisecond range) between microtubules and Tau. This mechanism was described for axonal microtubules in cultured neurons and seems to be essential for axonal transport [ 68 , 71 , 75 ]. Moreover, this region also interacts with other proteins, such as actin or heat shock proteins [ 76 , 77 ].…”

Phosphorylated Tau in Alzheimer’s Disease and Other Tauopathies

“…A growing body of evidence suggests that oxidative stress is one of the reasons for tauopathies; oxidative stress plays an essential role in tau hyperphosphorylation, polymerization, and tau toxicity [ 11 ]. Tau aggregates show different morphological and biochemical features in tauopathies [ 12 ]. The objectives of this article are to summarize the role of tau in microtubule structure and function, post-translational changes, and the pathological role of tau in AD and tauopathies.…”

mRNA Metabolism in Health and Disease

“…Martin’s group review [ 4 ] is focused on tau mRNA metabolism in neurodegenerative disorders. These authors discuss how abnormal tau mRNA metabolism, expression and dysregulation of tau post-translational modifications are associated with these disorders, as well as how tau protein interaction with RNA-binding proteins affects cellular mRNA metabolism.…”