Reprogramming protein quality control to protect against neurodegeneration

Similar to how quality control in manufacturing ensures that the products we use are made with consistency and meet specific standards, the cells in our bodies also have quality control mechanisms in place. An important role of cellular quality control is to safeguard our bodies against the accumulation of misfolded and neurotoxic proteins that can contribute to the progression of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). A report published in Nature Neuroscience identifies a set of new regulators of cellular quality control that is critical for proteins related to ALS and frontotemporal dementia (FTD). The study, led by a group of students and fellows, including Yu-Ning Lu, Goran Periz, and Jiayin Lu, from the lab of Jiou Wang, PhD, reports the team’s groundbreaking findings that are a result of over a decade of hard work.    

In order to understand signaling pathways and test the safety and efficacy of new therapies for human diseases like ALS, scientists often rely on model organisms. Rodent models of ALS are commonly utilized in research, but sometimes it is even impractical to use small mammals because it can take months and years for them to develop signs of disease. To bypass the time-consuming mouse studies and expedite research efforts, Wang’s team turned to a very unlikely ALS model system – the worm!  In 2009, Wang’s group published their pioneering experiments in which they incorporated an ALS gene into a worm that caused rapid motor impairments and allowed his team of researchers to study the genetics of ALS more quickly and easily. Utilizing their worm model for the present studies, Wang’s laboratory induced hundreds of thousands of different mutations into ALS worms and evaluated the worms to determine which mutations improved the physical impairments of ALS worms. This key experiment allowed Wang’s team to discover a gene that, when turned off, improves both motor deficits and protein aggregation that are characteristic of ALS.  The scientists confirmed that the gene identified in helping the ALS worms has a homolog, or corresponding gene with the same function, in small mammals and humans called L3MBTL1, making their worm discovery applicable and translatable to humans.

The next steps that the research team took involved cell culture studies to better understand the protein signaling pathways in which L3MBTL1 is involved. Cells have the ability to degrade or trash damaged proteins, and investigators learned that L3MBTL1 is important in regulating those quality control processes. They also identified another regulator of protein quality control in a similar signaling pathway called SETD8.  The scientists then used a mouse model of ALS, brain and spinal cord tissue samples from human ALS patients, and even a fly model of ALS to comprehensively confirm the role of these two modulators of protein quality control in the pathogenesis of ALS and related neurodegeneration. According to Wang “Protein levels of L3MBTL1 and SETD8 appear to be upregulated in human patients, suggesting they are already part of a natural defense compensatory mechanism, or maybe their function is perturbed in ALS.”  Knowing that these proteins are upregulated in ALS, the researchers then tested the effects of an inhibitor of L3MBT1 and found protection against proteotoxicity in neuronal cultures and improvements in motor function in the mouse model of ALS.  While this small molecule inhibitor of L3MBT1 is not yet available to be used as a treatment for human ALS, these proof-of-concept experiments are an exciting and critical first step to develop an effective human therapy.

When asked about his laboratory’s future research directions, Wang said he specifically wants to learn, “more about the sweet spot of where we can identify targets or design drugs that can control the defense mechanisms to protect the cells against proteotoxic stress.” Wang is hopeful that the benefits of his laboratory’s 10-year research endeavor will extend beyond the ALS/FTD community.  Because his team’s work, “doesn’t target one specific protein but instead identifies a larger pathway at work in ALS and other diseases where protein aggregation causes neurotoxicity,” they hope that this is a strategy “that might provide insight and benefit for a broad spectrum of neurological diseases.”

Adapted from Kristen Hollinger’s news report.