Annan, Leonette Victoria Naakuma Delali; (2017) The pathophysiology of Spinal Bulbar Muscular Atrophy: a longitudinal analysis of muscle and spinal cord. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Spinal Bulbar Muscular Atrophy (SBMA), also known as Kennedy's disease, is an X-linked, late-onset progressive neurodegenerative disease. SBMA is characterised by the selective loss of spinal and bulbar motor neurons and progressive muscle weakness. The disease is caused by an expansion in the CAG repeat in the androgen receptor (AR) gene which encodes a polyglutamine tract in the protein. The underlying pathophysiology of the disease is thought to be related to abnormal accumulation of the pathogenic AR protein within the nucleus. The AR100 transgenic mouse model of SBMA has a progressive neuromuscular phenotype accompanied by motor neuron degeneration, thereby mirroring the human disease. Since ER stress has been suggested to play a role in motor neuron death in SBMA, I investigated the underlying mechanism by which ER stress may result in cell death. In particular, I tested whether the motor neuron-specific Fas/NO cell death pathway plays a role in SBMA. In addition, I examined whether the ER chaperone, Calreticulin forms a link between the Fas/NO MN-specific death pathway and ER stress. I found that Fas/NO induced cell death is not observed in AR100 MNs. However, an increase in Calreticulin is observed in the spinal cord of AR100 mice, suggesting it may contribute to SBMA pathology. Although SBMA is considered to be a neurodegenerative disease affecting motor neurons, emerging evidence suggests that SBMA may also involve a primary muscle deficit. I examined this possibility by characterising muscle histopathology longitudinally, at different stages of disease progression, in AR100 mice. My results show that muscle atrophy is evident during early stages of disease, prior to any loss of motor neurons. Physiological deficits were accompanied by a change in the properties of the muscle fibres such as increase in oxidative capacity and signs of myogenic and neurogenic induced muscle atrophy. Furthermore, RNA-sequencing and pathway enrichment analysis of hindlimb muscles of AR100 mice identified some of the molecular signalling pathways which may underlie the changes within the muscle. These findings indicate that muscle deficits are an early and primary manifestation of disease in SBMA.

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