Cutting losses in ALS

Studies investigating how C9orf72 mutations cause amyotrophic lateral sclerosis (ALS) have largely focused on toxic gain-of-function mechanisms driven by the abnormal transcripts, which contain repeat expansions of various sizes. But C9orf72 mutations also result in lower protein levels, raising the possibility that loss of function could actually cause the disease.Now, a flurry of recently published papers have sized up the contribution of the loss of function to ALS and shown that while lower levels of the protein are not the primary disease driver, they likely contribute to inflammation in the brain. The findings warn against developing therapies that further decrease levels of the protein.

The most common cause of ALS, accounting for roughly 40% of familial cases and 8% of sporadic cases, involves expansion of the GGGGCC repeat sequence in the first intron of chromosome 9 open reading frame 72 (C9orf72). The expansion mutation is autosomal dominant, with patients typically carrying one mutant allele and one normal allele. However, sorting out how the mutation causes the disease is tricky because it could lead to a toxic gain of function, a loss of function due to haploinsufficiency of the normal protein, or both. ...