Disentangling the role of neural circuits in ALS

Dr. Santiago Mora Parada, a postdoc in Professor Illary Allodi’s lab at St Andrews, discussed his research on amyotrophic lateral sclerosis (ALS), a disease characterized by the progressive degeneration of the brain and spinal cord – the same disease Stephen Hawking was diagnosed with at age 21. Commonly believed to mainly affect motor neurons, Santi showed that the issue lies not in the motor neurons themselves, but rather impaired communication from spinal V1 inhibitory interneurons.

Most of the body becomes paralysed in ALS patients, except for muscles in the eye. This was thought to be due to high levels of Esyt1 protein expression, a protein involved in calcium ion channels of pre-synaptic neurons. When translated to ALS mouse models (Engrailed-1 and SOD1 models), the artificial overexpression of Esyt1 via viral vectors ameliorated the impaired connectivity between interneurons and motor neurons, resulting in improved motor function (limb angles and speed). However, this treatment did not improve survival rates, only quality of life.

These results were validated with machine learning and transcriptome analysis (i.e. RNAscope). In the next 30 years, we can look hopefully forward to antisense oligonucleotide therapies for treating human patients with ALS.