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May 23
2019

Slow and steady to understand ALS: insights from a new mouse model

Research Bytes
 A recent study by Packard Center Investigator Fen-Biao Gao describes a new and innovative mouse model of ALS-FTD that uncovers a novel mechanism as to how the disease degeneration progresses.

Animal research is an important part of studying diseases like amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and much of the critical work that goes into understanding disease pathogenesis relies on mouse models of the disease.  A study published last week in Nature Neuroscience conducted by Packard Center Investigator and Professor at the University of Massachusetts Medical School, Dr. Fen-Biao Gao describes a new and innovative mouse model of ALS-FTD generated by his laboratory that uncovers a novel mechanism as to how the disease, and in particular, the frontotemporal degeneration progresses.

There are, of course, many obvious differences between you and a mouse – a tail, for one! – but there are also many similarities as to how the cells in our brains function that make mice useful for studying neurodegenerative diseases.  Mice don’t get ALS or ALS-FTD like humans do, but scientists can genetically engineer mice to overexpress genes that cause human ALS, such as SOD1, or ALS-FTD like C9ORF72, that lead to disease-like symptoms and pathologies in the mice. The onset of symptoms in genetically engineered mice, however, is often very rapid and severe, which makes studying the cellular mechanisms impacted by gene mutations more difficult.  As Dr. Gao explains, “When you overexpress something you dramatically damage multiple cellular pathways simultaneously, so it’s not an ideal way to study disease mechanisms.”  Therefore, Dr. Gao and his team worked backwards to generate a new model that develops characteristics of ALS-FTD more slowly, thereby allowing the researchers to tease apart the exact events leading to the death of neuron cells in the brain and spinal cord.    

A common feature of human disease is the aggregation of toxic proteins in neurons.  Previous work has shown that one such protein called poly(GR) is both highly toxic in cultured cells and fruit flies as well as present in large number in the brains of ALS-FTD patients with the C9ORF72 mutation.  Dr. Gao’s laboratory found a way to induce the accumulation of poly(GR) in mouse brains very slowly.  They found that mice expressing only 5-15% of the levels of poly(GR) that are found in the brains of human ALS patients already had social- and anxiety-related behavioral deficits (mimicking aspects of FTD) and pathology in their brains that was causing some neuronal death.  By catching the disease process in its early stages, they were then able to look at specific substructures of neurons called mitochondria and identify morphological and functional deficits that are causing the behavioral problems and cell death.  In a final set of experiments, the scientists showed that these processes are reversible.

There are many exciting implications of Dr. Gao’s work for ALS and other diseases.  By identifying a specific pathway that contributes to cell death in ALS-FTD, researchers can now try to alter the pathway to prevent or rescue disease. Exploring and better understanding this line of work and developing a drug to boost mitochondrial function are future directions of Dr. Gao’s team.  Although the present studies utilized poly(GR), which is specific to C9ORF72 ALS, Dr. Gao stresses that “the pathway involving mitochondrial defect is common in almost all neurodegenerative disorders,” making this work potentially applicable to other neurodegenerative diseases like Alzheimer’s disease. 

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