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Investigation of selective vulnerability of motor neurones in spinal muscular atrophy

Investigation of selective vulnerability of motor neurones in spinal muscular atrophy
Wen-Yo Tu

2017

Sheffield Institute for Translational Neuroscience, The University of Sheffield, Sheffield, South Yorkshire S10 2TN, UNITED KINGDOM.

ABSTRACT

Spinal muscular atrophy (SMA), a leading genetic cause of infant death, is a neurodegenerative disease characterised by the loss of motor neurones in the anterior horn of the spinal cord with concomitant muscle weakness. However, a growing body of evidence shows that different motor pools in the anterior horn have a very different vulnerability to SMA. For example, previous studies on mouse have suggested motor neurones innervating three different muscles in the lower leg, tibialis anterior (TA), extensor digitorium longus (EDL) and gastrocnemius (GS) show different levels of axonal degeneration upon Smn loss. It indicated that there were undiscovered factors endeavouring motor neurones with distinct disease resistance.

As such, we attempted to discover these disease-modifying factors mainly by investigating the transcriptomes of different motor neurones with differing vulnerability. Further functionality experiments were carried out on both in vivo and in vitro systems to validate the microarray result. Furthermore, various new techniques were also tested to advance research in the future.

In general, we identified that higher bioenergetics could be the potential disease modulator, which was further illustrated by the manipulation of this pathway in zebrafish. However, bioenergetics status of the motor neurone was independent of SMN levels and likely to be a result of complex interaction of motor neurone and the surrounding environment in which astrocyte might play an important role. Moreover, the use of DEPArray (dielectrophoresis array) might offer an opportunity to explore this subject ex vivo. Lastly, because axon terminal tends to degenerate prior to the cell body, we extended the concept of selective vulnerability to motor neurone itself and attempted to specifically profile axonal transcriptome using RNAseq combined with the microfluidic device.