The cellular mechanisms from hyperexcitability to neurodegenerative pathologies are proposed in this paper.
- Tau pathology. Hyperexcitability may cause Ca2+ overload, resulting in activation of glycogen synthase kinase-3β (GSK-3β) and
cyclin dependent kinase 5 (Cdk5), which then phosphorylate Tau at specific sites to open the paperclip conformation of the Tau protein such that
its phosphatase-activating domain (PAD) is exposed. The PAD-exposed Tau proteins, whether they are monomeric or in an aggregate, may activate other GSK-3β
via protein phosphatase 1 as they diffuse within the cell or spread to other neurons. Hyperactive GSK-3β is toxic to neurons because it can impair axonal transport,
neurite outgrowth, and long-range synchronization.
- Beta amyloid (Aβ) pathology. The reciprocal interactions between Ca2+-induced reactive oxygen species (ROS) and ROS-modulated Ca2+ upsurge
may aggravate oxidative stress which has been demonstrated to promote the production of Aβ peptides. Aβ oligomers may bind the prion protein to induce mGluR5 signaling,
eventually resulting in hyperphosphorylation of CRMP2 which could be the major cause of Aβ-mediated synaptic deficits.
- α-Synuclein pathology. The hyperexcitability-induced hyperactive GSK-3β can phosphorylate α-synuclein at serine-129 (S129).
Strikingly, about 90% of α-synuclein found in pathological Lewy bodies are phosphorylated at S129, suggesting the importance of S129 phosphorylation in α-synuclein pathology.
- TDP-43 pathology. Abnormal TDP-43 may down-regulate miR-132 and miR-9, resulting in impaired TDP-43 clearance and dysregulation of neurofilaments, respectively.
The abnormal TDP-43 (pathological phosphorylation or cleavage) could also arise from hyperexcitability-induced Ca2+ overload.
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