Objective/Rationale:
Microtubules are critical components within nerve cells, where they serve as the “railroad” tracks upon which cellular cargo is transported up and down the length of the cells. Evidence from Parkinson’s disease (PD) model systems suggests that nerve cell function may be compromised in the disease as a result of microtubule deficits. We propose to examine novel cell culture and transgenic pre-clinical models of PD to further explore whether microtubule structure and function is altered, and to determine whether the microtubule-stabilizing agent, epothilone D, provides benefit in these models.
Project Description:
The major pathological feature within nerve cells of the PD brain is insoluble protein “clumps” comprised of alpha synuclein, which are referred to as Lewy bodies. We will use unique cell model of PD, in which nerve cells develop Lewy body-like deposits, to determine whether there is evidence of faulty microtubules. Moreover, we will test whether the microtubule-stabilizing drug, epothilone D, which is currently being tested in Alzheimer’s disease patients, might improve microtubule function in these nerve cells. Similarly, we will analyze a transgenic pre-clinical model, which also develops Lewy body-like deposits in nerve cells, for deficits in microtubule structure and function, and determine whether epothilone D provides benefit to these transgenic models.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
Obtaining further evidence of microtubule abnormalities in models of PD will provide important evidence that microtubule-stabilizing agents might hold promise for the treatment of this disease. We have previously demonstrated that the microtubule-stabilizing drug, epothilone D, provides significant benefit in transgenic pe-clinical models of Alzheimer’s disease (AD), and this drug is now undergoing clinical testing in AD patients. Thus, success in this project would suggest that epothilone D might also merit testing in patients with PD.
Anticipated Outcome:
The proposed studies should provide additional insight as to whether the presence of Lewy body-like deposits comprised of alpha synuclein cause changes within nerve cells that result in altered microtubule structure or function. In addition, the described experiments will provide data which will determine whether the microtubule-stabilizing agent, epothilone D, provides benefit in cell culture and transgenic pre-clinical models of PD.
Final Outcome
The aims of this project were to investigate whether microtubule changes were evident in cell culture and pre-clinical models that develop Lewy body-like aggregates such as those observed in nerve cells of Parkinson’s disease patients. Changes in microtubules were observed in a cell culture model in which the cells accumulate Lewy body-like inclusions, with an apparent increase in microtubule stability. Preliminary data also suggested that similar changes occurred in a model with Lewy body-like nerve cell inclusions. This led us to ask whether a drug that is known to modulate microtubule structure might “normalize” the microtubules in cells with Lewy body-like aggregates. We utilized a known agent called epothilone D, and unfortunately treatment with this drug did not appear to modulate the changes in MT structure observed in the cell culture model or improve outcomes in the model with Lewy body-like inclusions.
April 2014