A rare MAPT 3'-UTR haplotype confers resilience to FUS ALS
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which the nerve cells controlling movement, known as motor neurons, progressively die. Understanding the mechanisms of natural resilience is a promising, yet underexplored, avenue for developing therapies, especially for genetic forms of the disease where individuals with the same mutation can have vastly different outcomes. Here, we identify a protective genetic modifier by studying a unique family with a known ALS-causing gene mutation, in which several carriers remain completely healthy into their later years. Using a disease-in-a-dish model, we demonstrate that this rare haplotype in the gene encoding the protein Tau prevents motor neuron hyperexcitability and death by normalizing Tau protein levels. We reveal that this resistance is mediated by the subsequent regulation of calcium channels on the neuron's surface. Our study progresses from an observation of human disease resistance to a validated genetic modifier and a druggable downstream mechanism. This defines a Tau-calcium channel axis as a novel therapeutic target for ALS and provides a powerful paradigm for discovering protective factors in other incurable neurodegenerative disorders.