Wednesday, 26 August 2015

"Listen to the patient" - Sir William Osler

Science is great, but without the patients, we will learn nothing about disease. People with and without MND can help us fight the disease even after they have passed away. Today we published a paper that provides an example:

Motor neurone disease may be inherited, this is most commonly due to a mutation of the C9ORF72 gene. Autopsy studies of these cases seem to show classical features of MND - motor neurone loss with clumps of aggregated TDP-43 protein in residual motor neurones. In addition to these classical features, C9ORF72-related MND cases have clumps of protein that do not contain TDP-43 but do contain other proteins: mostly bizarre repeats of two amino acids alternating with each other: so-called dipeptide repeats (DPR). These clumps also contain some 'other stuff'. We don't know the full list of the 'other stuff' but would like to very much. 

A student who was studying with us in SITraN (Jo Bury) screened our collection of post mortem cases for mutations in a gene called optineurin. She found a mutation in one patient who also had a mutation in C9ORF72

There is lesson number one:
patients with inherited MND often have mutations in multiple relevant genes. We scientists need to stop thinking about "MND caused by mutations in this gene" and "MND caused by mutations in that gene". We need to start thinking about "MND caused by mutations in a number of genes".

As part of our study of this patient, we looked at where the optineurin protein was. It was incorporated along with TDP-43 in the classical inclusions. IT WAS ALSO tangled up in the DPR inclusions. 

Neurohistology from the spinal cord reveals optineurin incorporated
along with TDP-43 in the classical inclusions (arrow) found in the
cytoplasm of lower motor neurons in MND patients.

So we looked at other cases of MND caused by C9ORF72 muta
tions but without optineurin mutations. They too had optineurin protein in the DPR inclusions.

And there is lesson number two:
optineurin protein is present in the DPR inclusions of C9ORF72-related cases. It is part of the 'other stuff'. We need to work on optineurin and understand what it does in a cell and why. 

Optineurin protein is also present in the clumps of protein found in
C9ORF72-related MND together with dipeptide repeats.

We learned the importance of optineurin from a group of people who kindly donated their brain and spinal cord for research. By looking at these and comparing them to donations from people who do not have motor neurone disease, we learned an important lesson.

So here is a big "thank you" to everyone who has agreed to donate their brain and spinal cord after death. Thanks to everyone who has agreed to us having this tissue from their loved ones. Finally, we thank those who have passed away but are still fighting MND after they died by helping scientists in this way.  

The research presented here is now published in the journal Neuropathology:
Joanna J. Bury, J. Robin Highley, Johnathan Cooper-Knock, Emily F. Goodall, Adrian Higginbottom, Christopher J. McDermott, Paul G. Ince, Pamela J. Shaw and Janine Kirby (2015) Oligogenic inheritance of optineurin (OPTN) and C9ORF72 mutations in ALS highlights localisation of OPTN in the TDP-43-negative inclusions of C9ORF72-ALS. Epub 24 August 2015; DOI: 10.1111/neup.12240.

By J Robin Highley, Senior Clinical Lecturer in Neuropathology

Find out more about my research on the SITraN website.

You can follow me on Twitter @JRobinHighley and on ResearchGate.