Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the motor neuron. While most cases of ALS are sporadic, 10% are familial (FALS) with 20% of FALS caused by a mutation in the gene that codes for the enzyme Cu/Zn superoxide dismutase (SOD1). There is variability in sporadic ALS as well as FALS where even within the same family some siblings with the same mutation do not manifest disease. A transgenic (Tg) mouse model of FALS containing 25 copies of the mutant human SOD1 gene demonstrates motor neuron pathology and progressive weakness similar to ALS patients, leading to death at approximately 130 days. The onset of symptoms and survival of these transgenic mice are directly related to the number of copies of the mutant gene. We report the phenotype of a very low expressing (VLE) G93A SOD1 Tg carrying only 4 copies of the mutant G93ASOD1 gene. While weakness can start at 9 months, only 74% of mice 18 months or older demonstrate disease. The VLE mice show decreased motor neurons compared to wild-type mice as well as increased cytoplasmic translocation of TDP-43. In contrast to the standard G93A SOD1 Tg mouse which always develops motor weakness leading to death, not all VLE animals manifested clinical disease or shortened life span. In fact, approximately 20% of mice older than 24 months had no motor symptoms and only 18% of VLE mice older than 22 months reached end stage. Given the variable penetrance of clinical phenotype, prolonged survival, and protracted loss of motor neurons the VLE mouse provides a new tool that closely mimics human ALS. This tool will allow the study of pathologic events over time as well as the study of genetic and environmental modifiers that may not be causative, but can exacerbate or accelerate motor neuron disease.
Highlights
Amyotrophic lateral sclerosis (ALS) is a degenerative disease affecting primarily the motor neurons in the spinal cord, brainstem, and motor cortex
Not all very low expressing (VLE) animals manifested clinically evident disease or shortened life span with approximately 20% of mice older than 24 months not manifesting any symptoms of motor neuron disease
We have demonstrated that VLE mice carrying 4 copies of the mutant human G93A SOD1 gene on the mixed B6/SJL background have clinical motor and pathologic changes with neuronal loss and translocation of TDP-43 when compared to controls yet, not all of these animals demonstrate weakness or die at an earlier age
Summary
Amyotrophic lateral sclerosis (ALS) is a degenerative disease affecting primarily the motor neurons in the spinal cord, brainstem, and motor cortex. 177 ALS causing mutations have been identified in the human SOD1 gene. There is significant heterogeneity of the disease reported in FALS subjects with SOD1 mutations [3]. Some siblings of FALS patients, possessing the same SOD1 mutation, do not show signs of the disease [4]. The large variation in age of onset and severity in human ALS patients with specific SOD1 mutations lends support to the likelihood that there are other variables that determine disease expression. These variables likely include both environmental and genetic modifiers of disease [5,6]
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