Identification and functional characterisation of genes linked to motor neuron disease

Abstract

Motor neuron disorders are neurological conditions generally characterized by degeneration of motor neurons in the brain and spinal cord leading to skeletal muscle atrophy. Amyotrophic lateral sclerosis is the most common form of MND, comprising 80- 90% of cases. Owing to the success of large-scale genome-wide studies and technical advances in next generation sequencing, numerous genetic associations that predispose to the disease or modify disease progression have been identified, greatly influencing our understanding of this catastrophic disorder. Malta is home to an isolated population that is genetically homogeneous, a factor that is favourable to mine for founder ALS associated genes. To this end, a unique Malta ALS/MND Register and BioBank was set up and presently holds biological samples of Maltese ALS patients and age-sex-region matched controls. A high percentage of ALS patients are males and a significant amount experienced occupation-associated physical exertion. Several other patient population aspects are similar to those of neighbouring European countries, however a discrepancy in the Maltese genetic architecture is evident. In effect, the Maltese ALS patient cohort was found to be negative for deleterious variants in the four major ALS genes, C9orf72, SOD1, TARDBP and FUS. However, deleterious alleles were detected in minor, ALS genes, including ALS2, DAO, DCTN1, ERBB4, SARM1, SETX, SCFD1 and SPG11, genetically determining up to 40% of apparent sporadic ALS cases within the Maltese cohort. The effect of select damaging genes was analysed by generating animal models of ALS in an attempt to replicate disease phenotypes to strengthen the molecular understanding of pathogenic mechanisms associated with disease. As a result, the effects of DCTN1 and SCFD1 knockdown in Drosophila underscore a requirement of both genes for viability and normal neuromuscular function, which in part mimic the phenotypes observed in select Maltese ALS patients. Functional characterisation of population specific genes provides fundamental insights into the cellular pathways underpinning motor neuron degeneration in ALS. In turn, this facilitates the identification of therapeutic targets, particularly those directed towards personalised medicine.