Motor neuron degeneration and compensatory sprouting in mouse models of spinal muscular atrophy

Spinal muscular atrophy (SMA) is a childhood onset form of motor neuron disease. It is characterised by the degeneration and loss of lower motor neurons with subsequent muscle weakness and atrophy. It has long been assumed that these motor neurons degenerate in a distal to proximal manner, with the neuromuscular junction (NMJ) being an early pathological target. However, it is unknown how the onset of pathology at the distal portion of the motor neuron (the NMJ) relates to the onset of pathology at the proximal portion of the motor neuron (motor neuron cell body (MNCB)). Therefore, the timing of the onset of NMJ and MNCB pathology, in the Smn2B/- mouse model of SMA, is addressed within this thesis. The results show that NMJ pathology begins between P5 and P7 in Smn2B/- mice and MNCB morphology is altered in Smn2B/- mice between P10 and P15. Furthermore, the up-regulation of transcripts involved in the P53 signaling pathway is shown to coincide with the onset of NMJ pathology. Therefore whether NMJ pathology is the cause or a consequence P53 activation is subsequently investigated. By using an inducible P53 knock down Smn2B/- mouse model, it is shown that reducing P53 in Smn2B/- mice can decrease denervation. In this thesis, the possibility that the degeneration of motor neurons induces remaining motor neurons to sprout and whether it is this compensatory sprouting that allows certain muscles and mice to remain apparently ‘resistant’ to reduced Smn levels is also addressed. In mouse models and patients of SMA, some muscles are relatively spared, with lower levels of denervation even at late stages of disease. It is hypothesised that these ‘resistant’ muscles have increased motor neuron sprouting that compensates for ongoing denervation. To address this, degeneration and regeneration was quantified in resistant and vulnerable muscles in Smn2B/- mice as well as mouse models that have reduced Smn but are asymptomatic. The pathology of individual motor units was also assessed to determine whether there are compensatory populations of motor units. Furthermore, degeneration and regeneration in mouse models that have reduced Smn but are asymptomatic was quantified. In both of these cases, it was found that sprouting is not compensating for denervation in these ‘resistant’ muscles and mice, suggesting that these NMJs remain stable. Overall, these results provide an important insight into the pattern of motor neuron degeneration and remodeling in SMA and therefore provide significant contribution to the SMA research field