Amyotrophic lateral sclerosis (ALS) is finally in the spotlight. As a rare neurodegenerative disease characterized by the progressive loss of a subset of motor neurons, ALS has often been overshadowed by other diseases such as Alzheimer’s and Parkinson’s. However, thanks to events such as the viral Ice Bucket Challenge last summer and Eddie Redmayne’s Oscar winning portrayal of Stephen Hawking in The Theory of Everything, ALS has entered the public consciousness. In parallel, the scientific field has also experienced major growth, with new disease-causing mutations being reported on a regular basis. Labs have rushed to understand how these genetic mutations cause neurodegeneration, but a fundamental question remains unanswered: why do only certain motor neurons die in the course of ALS? After all, genetic mutations are global, and yet in ALS and most neurodegenerative diseases, only a subset of neurons die.
Smita Saxena and her lab at the University of Bern have worked to address this question of selective vulnerability for several years and have found that the neurons that degenerate in ALS may be intrinsically under more stress. In this latest paper from their group, Audrey Filézac de L’Etang and others set out to discover which molecules play a role in making neurons more or less vulnerable to disease. They discovered that a protein called SIL1 is highly expressed in disease-resistant neurons, and has low levels of expression in disease-vulnerable neurons. Intriguingly, SIL1 is known to protect neurons from stress, suggesting that the inherently lower levels of SIL1 in vulnerable neurons are why they die in ALS. In support of this, when Filézac de L’Etang et al. genetically reduced levels of SIL1 in normal mice, there was increased neuronal stress and motor neuron recovery from injury was significantly impaired.
Compelling as this evidence may be, it only suggests; it does not establish causality. Therefore, Filézac de L’Etang et al. then altered SIL1 levels in a mouse model of ALS and examined disease progression. They found that decreasing SIL1 in the ALS mice accelerated the disease process, with faster decline in motor coordination and decreased lifespans. On the flip side, increasing SIL1 in the ALS mice alleviated the disease, with improved coordination and increased lifespans. Furthermore, increasing SIL1 led to survival of the motor neurons that typically die in ALS. With these two experiments, Filézac de L’Etang et al. have shown that certain neurons can be biased for degeneration depending on their molecular composition and that altering said composition can rescue the neurons from death in a mouse model of ALS.
These findings are exciting, as they help answer one of the long-standing issues in the field of neurodegeneration. Certainly, there are still some unanswered questions that need to be addressed in future studies – how do the variety of mutated ALS genes interact with SIL1 and cellular stress? Are there other regions of the brain that have low SIL1 and if so, are they lost in ALS? Can SIL1 explain selective vulnerability in other neurodegenerative diseases? Nevertheless, this study is a critical advancement in our understanding ALS, making a cure that much closer.