|The Role of Microtubules and Tau Proteins in Neuronal Excitability|
For more than three decades, the evidence (Matsumoto and Sakai, 1979) that microtubules might play a role in neuronal excitability has been largely ignored. This situation was changed a few years ago, when several groups provided direct evidence for the involvement of microtubule-associated protein Tau in excitability. Since then, further evidence continues to accumulate. The microtubule-depolymerizing agent nocodazole has been demonstrated to reduce burst activity and seizure severity. Very recently, Hatch et al. (2017) showed that the hyperphosphorylated Tau could reduce excitability by modulating the axon initial segment (AIS) in a microtubule-dependent manner. These findings support the microtubule (MT) model proposed in Paper 1. This paper will extend the MT model to explain (1) how excessive 4-repeat Tau may cause hyperexcitability, and (2) how seizures can be terminated by the detyrosinated tubulins which are disassembled from microtubules at AIS.
(2017-2-23). It has been known for several decades that the toxicity of oligomeric α-synuclein plays a key role in Parkinson's disease. A plethora of possible mechanisms were proposed (Roberts and Brown, 2015). Ten years ago, experimental studies have demonstrated that oligomeric α-synuclein inhibits tubulin polymerization (Chen et al., 2007), but the link between Parkinson's disease and microtubule/tubulin did not receive much attention until recently (Cartelli et al., 2016; Oikawa et al., 2016; Brunden et al., 2016; Ballatore et al., 2017; Blanca et al., 2017; Pellegrini et al., 2017). According to the MT model for excitability presented in this paper, inhibited tubulin polymerization at the axon terminal of a dopaminergic neuron should reduce burst activity at the terminal, thereby decreasing dopamine release, which is the hallmark of Parkinson's disease. Consistent with this view, intracellular oligomeric α-synuclein has been shown to reduce pyramidal cell excitability (Kaufmann et al., 2016).
(2017-4-8). Erratum: the words "A tubulin dimer contains about 50 negatively charged residues" should read "A tubulin dimer contains about 50 more negatively than positively charged residues".