Microtubule Stabilizers as Modifiers of Alpha-Synucleinopathy.

Lewy body disorders are associated with hallmark inclusions containing aggregated forms of alpha-synuclein. When alpha-synuclein aggregates in the synapse, it may be transported along axonal microtubular tracks to the soma for degradation or deposition into insoluble inclusions. However, during this transportation, alpha-synuclein aggregates may also adhere to the microtubules and impede the axonal transport of other cellular constituents. Axonal transport is known to depend upon the stability of the microtubule tracks, but the specific impact of alpha-synucleinopathy on microtubular dynamicity is unclear. Here, we assessed markers of microtubule stabilization in olfactory bulb and amygdala samples harvested postmortem from men and women with Lewy body disorders and age-matched control subjects. Unexpectedly, we observed that women showed higher levels of detyrosinated alpha-tubulin (marker of microtubule stability) as well as higher levels of tyrosinated alpha-tubulin (marker of non-stabilized microtubules) compared to men. Second, the impact of microtubule stability on inclusion body formation is also poorly understood. Thus, we measured inclusion counts in primary hippocampal cultures treated with novel heterocyclic microtubule stabilizers and challenged with preformed alpha-synuclein fibrils. As expected, the microtubule stabilizers reduced pathologically phosphorylated (pSer129) alpha-synuclein+ inclusion counts, and the microtubule destabilizer nocodazole prevented this reduction in pathological inclusions. These collective data suggest that microtubule stability may influence the emergence of alpha-synucleinopathy in experimental Lewy body disease.