Geon Neurodegeneration: From Hyperexcitability to
Pathologic Tau, TDP-43 and α-Synuclein



Amyotrophic lateral sclerosis/parkinsonism-dementia complex of Guam (ALS/PDC) is caused by misincorporation of β-N-methylamino-L-alanine (BMAA) into normal proteins, resulting in protein misfolding. Experiments have shown that protein misfolding may promote mTOR activation, leading to hyperexcitability (Paper 3). ALS/PDC exhibits Tau, TDP-43 and α-synuclein pathology, suggesting that these pathologies could originate from hyperexcitability. The underlying mechanisms are discussed in this paper. Although Ca2+ toxicity is a common consequence of hyperexcitability, the specific pathology depends on the neuronal compartment where Ca2+ enters the neuron. For Tau pathology, which occurs in the neurons containing "microtubule antennas" for long range synchronization (Paper 1), Ca2+ is likely to enter the neuron through T-type calcium channels at the axon initial segment, resulting in calpain activation and consequently leading to Tau hyperphosphorylation by GSK-3 or CDK5. The TDP-43 pathology may result mainly from over-stimulation of Ca2+-permeable AMPA receptors at the dendritic spines that synapse with neurons participating in long range synchronization. In Parkinson's disease, the α-synuclein pathology occurs in the dopaminergic (DA) neurons of substantia nigra pars compacta (SNc), resulting from glutamate-mediated hyperexcitability which causes excessive Ca2+ influx through L-type calcium channels at axon terminals. The Ca2+ overload in DA neurons promotes α-synuclein aggregation, which inhibits tubulin polymerization into microtubules. As discussed in Paper 2, the highly negatively charged tubulin can regulate excitability. Elevated tubulin at the axon terminal should attenuate excitability, thereby reducing dopamine release.


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(2017-5-12). LRRK2 and Parkin, two proteins implicated in Parkinson's disease, have been demonstrated to interact directly with tubulin. Their interaction may modulate neuronal excitability. See "The Role of Tubulin in Parkinson's Disease".