Posted May 6, 2016
Leonard Petrucelli, Ph.D., Mayo Clinic College of Medicine, Jacksonville FL

With support from an ALSRP FY13 Therapeutic Development Award, Dr. Leonard Petrucelli and his team developed the first mouse model to exhibit behavioral and neuropathological characteristics associated with the most common genetic form of amyotrophic lateral sclerosis (ALS, Lou Gehrig's disease) and frontotemporal dementia (FTD), which are caused by a mutation in the gene "chromosome 9 open reading frame 72" or C9ORF72. This mouse model sheds light on the adverse events caused by the C9ORF72 mutation - information important in moving the ALS research community closer to finding effective therapeutics.

ALS is a progressive and degenerative disorder of motor neurons that results in paralysis, muscle atrophy and, eventually, death. ALS can be either sporadic, occurring apparently at random without known associated risk factors, or familial, the inherited form of the disease. In the 5% to 10% of ALS cases that are inherited, approximately one-third results from a defect in the C9ORF72 gene. More specifically, C9ORF72 mutation carriers have a longer than usual repeating sequence in the DNA that encodes the gene. These long hexanucleotide G₄C₂ repeats cause the accumulation of toxic ribonucleic acid (RNA) species that either cluster into structures called foci or cause the production of abnormal proteins (c9RAN proteins) in the brain and spinal cord of patients. Another pathological hallmark of patients with ALS or FTD, including those with the C9ORF72 mutation (c9ALS/FTD), is the presence of clumps of the TDP-43 protein in cells of the brain and spinal cord. Deciphering the link between the C9ORF72 mutation and TDP-43 pathology, as well as establishing how the C9ORF72 mutation causes neurodegeneration, are key goals of the ALS and FTD fields.

To gain insight into these and other important questions regarding c9ALS/FTD, Dr. Petrucelli and collaborators produced mice that express an expanded G₄C₂ sequence, namely 66 G₄C₂ repeats, in their brain and spinal cord. As a control group, mice that express only 2 G₄C₂ repeats were made. The researchers observed that the (G₄C₂)₆₆ mice developed neuropathological and clinical phenotypes of c9ALS/FTD. As in c9ALS/FTD patients, RNA foci, c9RAN proteins and even TDP-43 pathology were present in the brain of (G₄C₂)₆₆ mice, and these features were accompanied by neuron loss and brain atrophy. What is more, (G₄C₂)₆₆ mice developed signs of hyperactivity, anxiety, anti-social behavior and motor deficits, which mirror patient symptoms.

The creation of a mouse model that reflects the neuropathological changes and neurodegeneration of c9ALS/FTD is a big step towards understanding c9ALS/FTD pathogenesis. These mice also offer an attractive model for identifying diagnostics and testing potential therapeutics targeted towards G₄C₂ RNA, key objectives of Dr. Petrucelli's scientific program. Indeed, together with collaborators, Dr. Petrucelli identified small molecules that can block the abnormal formation of RNA foci and c9RAN proteins in patient-derived cell models. Notably, the somewhat unexpected but fortuitous finding that expression of expanded G₄C₂ repeats is sufficient to cause TDP-43 pathology suggests that such small molecules and other therapeutic approaches may not only mitigate the production of RNA foci and c9RAN proteins, but also alleviate TDP-43 toxicity in c9ALS/FTD.

Publication:

Chew J, Gendron TF, Prudencio M, et al. 2015. C9ORF72 repeat expansions in mice cause TDP-43 pathology, neuronal loss, and behavioral deficits. Science 348(6239):1151-1154. doi:10.1126/science.aaa9344.

Links:

Public and Technical Abstracts: Inhibitors of c9RAN Translated Peptides and Toxicity in c9FTD/ALS

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