‘I am a final year PhD student studying Amyotrophic Lateral Sclerosis (ALS). I attended the 25th international symposium on ALS/MND Brussels, Belgium on 5-7 December 2014. The conference was very beneficial for my development as a researcher. Presenting my work in the poster sessions allowed me to network with other researchers in the field. Attending the oral and poster presentations has kept me up to date with the latest work, and listening to many passionate researchers and clinicians in the field has really enthused me as a researcher. I thank the Biochemical Society for providing me with a travel grant that allowed me to attend the conference.
Many areas of ALS research are advancing rapidly, and there are several molecular pathways emerging that could hold the key for future therapeutics. John Hardy’s talk highlighted how many mutations that cause ALS are found in genes that regulate autophagy. In addition, TBK1 (a protein involved autophagy regulation) was revealed as the latest ALS gene. Hadano showed that knocking out p62 (an autophagy regulator) in a SOD1 H46R ALS mouse model reduced lifespan, and increased motor dysfunction and caused axonal degeneration in the spinal cord – suggesting autophagy is protective against misfolded SOD1 protein. Unexpectedly however, a study by Perera showed rilmenidine (an autophagy activating drug) actually accelerated disease progression in SOD1 G93A ALS mice. Finally, Chris Webster showed C9ORF72 protein binds components of the autophagy initiation complex and functional data implicating C9ORF72 in autophagy initiation.
In my PhD project I am studying a hexanucleotide (GGGGCC)n repeat expansion found within intron 1 of C9ORF72. It was hugely beneficial to listen to the cutting edge research in my field, because it is moving so quickly! Ranum presented work supporting the Dipeptide repeat (DPR) proteins as the toxic entity in C9ORF72 ALS/FTD. Whilst Cooper-Knock presented data supporting RNA toxicity. He showed that TDP-43 mislocalisation correlates with antisense (CCCCGG)n RNA but not sense (GGGGCC)n RNA in C9ORF72-ALS CNS tissue. De Muynck showed that increased transcription of C9ORF72 containing the (GGGGCC)n repeat expansion correlated with more rapid disease progression, again supporting both RNA and DPR toxicity. IPG Award winner Lagier-Tourenne presented a two different CORF72-ALS mouse models to interrogate C9ORF72 haploinsufficiency, RNA toxicity and DPR toxicity. She showed loss of C9ORF72 protein does not cause apparent motor phenotype or disease. Whilst mice expressing (GGGGCC)n constructs exhibited cognitive defects, but no motor defects.
My favourite piece of research was presented by Kevin Eggan. He showed a ground breaking gene correcting technique in induced pluripotent stem cells (iPSC) derived from SOD1 A4V ALS patient fibroblasts. The technique converts a pathogenic gene variant (SOD1 A4V in this case) back to wild type in the iPSC, producing isogenic controls cells. This type of genetic engineering will drastically remove experimental noise and improve drug screening efforts. Further, they used optogenetic technology to show retigabine (an anti-epileptic drug) reduced excitability and improved viability of SOD1 A4V iPSC derived motor neurons. Retigabine is now being taken forward for clinical trials, and this work shows the true power of iPSCs models for finding therapeutics.’