Date of Award

Spring 2012

Degree Type


Degree Name

Doctor of Philosophy (Medical Science)


Medical Sciences (Neurosciences)


John Turnbull



Committee Member

Laurie Doering


Amyotrophic Lateral Sclerosis (ALS) is a fatal progressive neurodegenerative disease with no known cause. Despite the efforts of investigators over the past 150 years, there remains no effective cure which substantially prolongs life. Therapeutic strategies have explored all of the proposed underlying pathological pathways of the disease from increased oxidative damage to impaired axonal transport, with little to no success. In the following pages, a novel perspective will be presented outlining the preliminary investigations of a new line of research demonstrating that Sonic hedgehog (Shh) protein and its agonists have cytoprotective effects on motor neurons. To begin these investigations, initial experiments were conducted in vitro utilizing a mouse hippocampal cell-line (HT-22) which served as a model for transient transfection and oxidative challenge assays. The results are reported in Chapter 2. Building upon these introductory findings, further investigations were conducted exploiting the SOD1G93A mouse model of ALS. Chapter 3 summarizes key observations pertaining to the abundance of a key cellular organelle in the sensing of Shh signalling, the primary cilium, in the spinal cord of SOD1G93A mice. In Chapter 4, a semi-quantitative analysis of the effects of Shh and Shh agonists pre-treatment in vitro on primary mixed spinal cord cultures are described. Subsequent challenge with an excitotoxic NMDA treatment was also conducted, as well as an in vivo survival study exploring the potential therapeutic effects of chronic Shh administration on SOD1G93A mice. The cumulative research presented here represents the very first investigation into the unique application of Shh and its agonists as potential therapeutic agents for the treatment of ALS, and our findings indicate that Shh has the potential of becoming a novel therapeutic agent for the treatment of ALS.

McMaster University Library

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