Monday, 9 January 2017

SITraN 2016 review

Happy New Year! A lot happened in 2016, the staff and students here at SITraN have been working to develop disease-modifying therapies for neurodegenerative diseases. There were numerous papers published by SITraN researchers last year (too many to name them all), so this is our yearly recap and summary of a select few…

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo
A. Seytanoglu, N. I. Alsomali, C. F. Valori, A. McGown, H. R. Kim, K. Ning, T. Ramesh, B. Sharrack, J. D. Wood, M. Azzouz.
Neuroscience 322 (2016) 287–297

Schwann cells are involved in protecting neuronal axons which are responsible for carrying electrical impulses and information between the body and the brain. They do this by wrapping themselves around axons to produce what is called the myelin sheath; think of the plastic jacket on a cable insulating the wires inside. Using a zebrafish model, the authors found that these Schwann cells were not developing correctly in a nerve when they knocked out a gene called GLE1, which is affected in lethal congenital contracture syndrome 1 (LCCS1). Zebrafish that had no Gle1 had less Schwann cells and therefore less insulation around their nerves and this may be contributing to disease pathology and could be an area of interest to focus research.

The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy

C. P. Webster, E. F. Smith, C. S. Bauer, A. Moller, G. M. Hautbergue, L. Ferraiuolo, M. A. Myszczynska, A. Higginbottom, M. J. Walsh, A. J. Whitworth, B. K. Kaspar, K. Meyer, P. J. Shaw, A. J. Grierson, K. J. De Vos

The EMBO Journal 35 (2016) 1597-1719

A mutation in the C9ORF72 gene is the leading cause of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia (C9ALS/FTD). The function of the C9orf72 protein was, until recently, unknown. One of the proposed theories for how the disease is caused is through reduced levels of the C9orf72 protein. This paper from the De Vos group finds that C9orf72 interacts with another two proteins called Rab1a and ULK1. Both these proteins are involved in a process called autophagy, which is a mechanism used by cells to remove unwanted or damaged parts. Further investigation found C9orf72 is specifically involved in inducing autophagy and when C9orf72 was reduced in cells, autophagy decreased. Finally, when they looked in neurons derived from C9ALS/FTD patients, autophagy appears to be reduced in comparison to healthy controls.

Evaluating a novel cervical orthosis, the Sheffield Support Snood, in patients with amyotrophic lateral sclerosis/motor neuron disease with neck weakness

S. Baxter, H. Reed, Z. Clarke, S. Judge, N. Heron, A. McCarthy, J. Langley, A. Stanton, O. Wells, G. Squire, A. Quinn, M. Strong, P. J. Shaw, C. J. McDermott.

Amyotrophic Lateral Sclerosis and Frontotemporal Degeneration 17 (2016) 436-442

To counter the neck weakness suffered by ALS patients, it is currently advised to wear a neck brace. Feedback from patients however highlighted several issues they faced in doing so, such as their restrictiveness. A project at SITraN was therefore set up to design a neck brace (pictured) that allowed patients more flexibility whilst maintaining its ability to support the neck. This paper from Dr Christopher McDermott’s team describes the response from 26 ALS patients who evaluated the new neck brace. The neck brace was received positively, with key beneficial features described as: increased support while providing a greater range of movement, flexibility of use, and improved appearance and comfort.


Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism
L. Ferraiuolo, K. Meyer, T.W. Sherwood, J. Vick, S. Likhite, A. Frakes, C.J. Miranda, L. Braun, P.R. Heath, R. Pineda, C.E. Beattie, P.J. Shaw, C.C. Askwith, D. McTigue, B.K. Kaspar.
PNAS 113 (2016) E6496-E6505
Oligodendrocytes are cells that help to maintain the health of neurons in the brain and spinal cord. Recent research suggests that oligodendrocytes play a role in ALS. To discover how this happens, the authors of this paper turned cells from ALS patients and healthy individuals into motor neurons and oligodendrocytes, and grew them together in a dish. When ALS oligodendrocytes were grown with healthy motor neurons, the neurons died.  The authors found that SOD1 (a protein known to behave abnormally in many ALS patients) is likely to impair the ability of oligodendrocytes to properly support motor neurons, causing the neurons to die. This research has provided important insights into the toxic role of oligodendrocytes in ALS, which will enable researchers to try and develop therapies to counteract these effects.

Gene expression profiling of the astrocyte transcriptome in multiple sclerosis normal appearing white matter reveals a neuroprotective role

R. Waller, M.N. Woodroof, S.B. Wharton, P.G. Ince, S. Francese, P.R. Heath, A. Cudzich-Madry, R.H. Thomas, N. Rounding, B. Sharrack, J.E. Simpson.
Journal of Neuroimmunology 299 (2016) 139–146

In multiple sclerosis (MS), myelin (an important insulating substance wrapped around axons) in the brain and spinal cord becomes damaged.  Areas of the brain containing myelinated axons are known as “white matter”.  In MS, white matter contains areas that are demyelinated (lesions) and some normal-appearing white matter (NAWM), which is not demyelinated.  This paper aimed to explore the role of astrocytes (supporting cells in the brain) in NAWM.  Some evidence suggests that astrocytes are protective in MS, but other research suggests that astrocytes might contribute to lesion formation.  To better understand the role that astrocytes play in MS, the authors investigated which genes are switched on or off in the NAWM astrocytes of MS patients.   Genes that were upregulated (more switched on) in MS patients compared to controls were associated with supporting neuronal health and controlling responses to oxidative and immune stresses, as well as regulating iron levels, suggesting that NAWM astrocytes are protective in MS.

This blog was written by PhD students Katie Adamson and Yolanda Gibson.
Twitter: @katie_adamson_ @YolandaGibson_