The work discussed in the following dissertation has sought to identify some of the roles of microtubules and microtubule-associated proteins in neurodegenerative conditions. The first part, describing the majority of my thesis work, has sought to identify cytoskeletal mechanisms associated with the development of chemotherapy induced peripheral neuropathy, while the second part discusses work aimed at understanding the role and function of the N-terminal region of the microtubule associated protein tau in normal and pathological conditions.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect from treatment of cancers with anti-neoplastic drugs like microtubule targeting agents (MTAs). CIPN symptoms include pain, numbness, tingling, and hypersensitivity to temperature and pressure that can become severe enough to necessitate dose reduction or cessation of treatment all together. However, onset, rate of progression, and severity vary greatly with the different classes of MTAs. As different MTAs have distinct mechanisms by which they bind to and alter microtubule dynamic function, we hypothesize these mechanistic differences may underlie the variability seen in CIPN symptoms. We utilized immunofluorescent microscopic strategies to identify critical drug-induced changes to tubulin and microtubule associated proteins in an effort to understand cytoskeletal alterations that may lead to the development of CIPN symptoms. Our findings have indicated that paclitaxel and eribulin induce unique morphological and molecular changes to peripheral sciatic nerves and dorsal root ganglia supporting our hypothesis that treatment drugs with different mechanisms result in distinct changes. Additionally, the comparison between drug-induced changes between sciatic nerve and dorsal root ganglia indicate that microtubules possess regionally specific functional properties.

The second part of the dissertation herein, describes work aimed at understanding the role and function of the amino-terminus of the microtubule associated protein tau. Fragments from the N-terminal region of tau have been found to be increased brain tissue from Alzheimer's disease (AD) patients as compared to tissue from non-AD brains, suggesting this region may play a role in AD pathology. This region has been hypothesized to be important for normal tau function in the assembly and bundling of microtubules, however the mechanisms by which it accomplishes this regulation remain unclear. Multiple lines of in vitro evidence suggest that this region may mediate the formation of tau-tau dimerization and oligomerization. We therefore hypothesize that N-terminal mediated dimerization may be a normal part of tau action in vivo and have sought to test this hypothesis both in in vitro and cell culture experiments. However, the findings reported in the following chapter did not provide evidence to support our hypothesis; rather, the N-terminal fragment studied here did not demonstrate disruption of normal tau function or overt neurotoxicity. This suggests the mechanisms of tau neurotoxicity may be more complex and will require further investigation.