Strategies for diminishing katanin-based loss of microtubules in tauopathic neurodegenerative diseases

Abstract

It is commonly stated that microtubules gradually disintegrate as tau becomes dissociated from them in tauopathies such as Alzheimer's disease. However, there has been no compelling evidence to date that such disintegration is due to depolymerization of microtubules from their ends. In recent studies, we have shown that neurons contain sufficient levels of the microtubule-severing protein termed katanin to completely break down the axonal microtubule array if not somehow attenuated. The presence of tau on axonal microtubules renders them notably less sensitive to katanin, prompting us to posit that microtubule disintegration in tauopathies may result from elevated severing of the microtubules as they lose tau. In support of this hypothesis, we demonstrate here that pathogenic tau mutants that bind less strongly to microtubules than wild-type tau provide correspondingly less protection against katanin-based severing. Using cultured rat hippocampal neurons, we pursued two potential therapies for fortifying axonal microtubules against excess severing by katanin, under conditions of tau depletion. We found that either deacetylating the microtubules via overexpression of HDAC6 or treating the neurons with NAP, a microtubule-interacting neuroprotective peptide, resulted in notable protection of the microtubules against katanin-based loss. In both cases, we found that these treatments also diminished the characteristic increase in axonal branching that normally accompanies tau depletion, an effect that is also known to be directly related to the severing of microtubules. These observations may be useful in developing therapeutic regimes for preserving microtubules against loss in the axons of patients suffering from tauopathies.

Microtubule-severing enzymes at the cutting edge

“…This observation has fueled speculation that the misregulation of katanin might contribute to tauopathies, such as Alzheimer's disease, which are hallmarked by tau hyperphosphorylation . Similarly, a very recent study has shown that katanin is inhibited by the neuroprotective peptide (NAP), which has been found to ameliorate some Alzheimer's disease symptoms in animal models (Sudo and Baas, 2011). In addition to its regulation by tau, katanin has been found to selectively attack acetylated microtubules (Sudo and Baas, 2010), which are abundant in the axon, and its expression levels have been shown to vary dramatically during neuronal development, namely peaking during periods of rapid axon outgrowth and falling precipitously thereafter (Karabay et al, 2004).…”

Building the Neuronal Microtubule Cytoskeleton

“…It is, for example, reported that tau binding to MTs protects them against katanin-mediated severing (Qiang et al, 2006). An interesting hypothesis is that the MT defects observed in tauopathies, such as Alzheimer's disease, may result from elevated severing of axonal MTs as they lose their tau binding (Sudo and Baas, 2011). Spastin activity is not strongly affected by tau, but is enhanced on polyglutamylated MTs (Lacroix et al, 2010).…”

Microtubules in health and degenerative disease of the nervous system

“…Such a mechanism would suggest that stable domains of microtubules become labile, which would then somehow lead to a degradation of the microtubule mass. Another theory posits that detachment of tau from microtubules causes them to become more sensitive to microtubule-severing proteins, mainly katanin (83, 84). There has also been evidence that tau tangles themselves can promote microtubule depolymerization (85), and the same could be true of soluble abnormal tau.…”