To better understand amyotrophic lateral sclerosis (ALS), we used sequence data from patients to identify novel disease-associated loci and in vivo studies to determine the biological effect of loss of Mitofusin 2 (MFN2) function in zebrafish.

BACKGROUND: ALS is a rapidly fatal, rare neurodegenerative disease typified by the loss of motor neurons in the motor cortex and spinal cord. Twin studies estimate the heritability of sporadic ALS (SALS) to be 61%, yet mutations in known mendelian ALS genes only account for 17% of SALS cases. MFN2 is a mitochondrial outer membrane protein and mitochondrial function is implicated in ALS pathology. Zebrafish have been used previously to model motor neuron disease.

DESIGN/METHODS: Sequencing data for 140 ALS patients were analyzed using VAAST and Phevor to identify genes burdened with rare, nonsynonymous variants. MFN2 was a top hit. We analyzed mfn2 knockout (KO) zebrafish, including movement assays and TDP-43 levels in brain lysates.

CONCLUSIONS: We identified MFN2 as a potential SALS-associated gene. In vivo zebrafish studies show motor and spine morphology consistent with known ALS phenotypes in zebrafish, as well as abnormal accumulation of TDP-43 in their brains.  Interestingly, MFN2 is a known cause of Charcot-Marie-Tooth Type 2A (CMT2A). We hypothesize that CMT2A and ALS are on a disease spectrum, and that MFN2 is a novel modifier of ALS pathology.