Clark, JA and Blizzard, CA and Breslin, MC and Yeaman, EJ and Lee, KM and Chuckowree, JA and Dickson, TC, Epothilone D accelerates disease progression in the SOD1G93A mouse model of amyotrophic lateral sclerosis, Neuropathology and Applied Neurobiology, 44, (6) pp. 590-605. ISSN 0305-1846 (2018) [Refereed Article]
Copyright 2018 British Neuropathological Society
Aims: Degeneration of the distal neuromuscular circuitry is a hallmark pathology of Amyotrophic Lateral Sclerosis (ALS). The potential for microtubule dysfunction to be a critical pathophysiological mechanism in the destruction of this circuitry is increasingly being appreciated. Stabilization of microtubules to improve neuronal integrity and pathology has been shown to be a particularly favourable approach in other neurodegenerative diseases. We present evidence here that treatment with the microtubule‐targeting compound Epothilone D (EpoD) both positively and negatively affects the spinal neuromuscular circuitry in the SOD1G93A mouse model of ALS.
Methods: SOD1G93A mice were treated every 5 days with 2 mg/kg EpoD. Evaluation of motor behaviour, neurological phenotype and survival was completed, with age‐dependent histological characterization also conducted, using the thy1‐YFP mouse. Motor neuron degeneration, axonal integrity, neuromuscular junction (NMJ) health and gliosis were also assessed.
Results: EpoD treatment prevented loss of the spinal motor neuron soma, and distal axon degeneration, early in the disease course. This, however, was not associated with protection of the NMJ synapse and did not improve motor phenotype or clinical progression. EpoD administration was also found to be neurotoxic at later disease stages. This was evidenced by accelerated motor neuron cell body loss, increasing gliosis, and was associated with detrimental outcomes to motor behaviour, clinical assessment and survival.
Conclusions: The results suggest that EpoD accelerates disease progression in the SOD1G93A mouse model of ALS, and highlights that the pathophysiological involvement of microtubules in ALS is an evolving and underappreciated phenomenon.
|Item Type:||Refereed Article|
|Keywords:||amyotrophic lateral sclerosis, epothilone D, microtubule stabilisation, toxicity, motor behaviour, microtubules|
|Research Division:||Medical and Health Sciences|
|Research Field:||Central Nervous System|
|Objective Group:||Clinical Health (Organs, Diseases and Abnormal Conditions)|
|Objective Field:||Nervous System and Disorders|
|UTAS Author:||Clark, JA (Mr Jayden Clark)|
|UTAS Author:||Blizzard, CA (Dr Catherine Blizzard)|
|UTAS Author:||Breslin, MC (Dr Monique Breslin)|
|UTAS Author:||Yeaman, EJ (Ms Elise Yeaman)|
|UTAS Author:||Chuckowree, JA (Dr Jyoti Chuckowree)|
|UTAS Author:||Dickson, TC (Professor Tracey Dickson)|
|Web of Science® Times Cited:||2|
|Deposited By:||Menzies Institute for Medical Research|
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