Abstract
BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by selective motoneurons degeneration. There is today no clear-cut pathogenesis sequence nor any treatment. However growing evidences are in favor of the involvement, besides neurons, of several partners such as glia and muscles. To better characterize the time course of pathological events in an animal model that recapitulates human ALS symptoms, we investigated functional and cellular characteristics of hSOD1G93A mice.Methods and FindingsWe have evaluated locomotor function of hSOD1G93A mice through dynamic walking patterns and spontaneous motor activity analysis. We detected early functional deficits that redefine symptoms onset at 60 days of age, i.e. 20 days earlier than previously described. Moreover, sequential combination of these approaches allows monitoring of motor activity up to disease end stage. To tentatively correlate early functional deficit with cellular alterations we have used flow cytometry and immunohistochemistry approaches to characterize neuromuscular junctions, astrocytes and microglia. We show that (1) decrease in neuromuscular junction's number correlates with motor impairment, (2) astrocytes number is not altered at pre- and early-symptomatic ages but intraspinal repartition is modified at symptoms onset, and (3) microglia modifications precede disease onset. At pre-symptomatic age, we show a decrease in microglia number whereas at onset of the disease two distinct microglia sub-populations emerge.ConclusionsIn conclusion, precise motor analysis updates the onset of the disease in hSOD1G93A mice and allows locomotor monitoring until the end stage of the disease. Early functional deficits coincide with alterations of neuromuscular junctions. Importantly, we identify different sets of changes in microglia before disease onset as well as at early-symptomatic stage. This finding not only brings a new sequence of cellular events in the natural history of the disease, but it may also provide clues in the search for biomarkers of the disease, and potential therapeutic targets.
Highlights
Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by a selective degeneration of motoneurons in the motor cortex, brainstem, and spinal cord
At 53 days of age hSOD1G93A animals presented the same pattern as controls (Figure 2A), whereas from 60 days onwards, they showed a subtle but constant alteration in gait pattern appearing as the inability to draw their hind limbs up to the previous position of their front limbs (Figure 1C and Figure 2B)
Using the CatWalkTM system, we demonstrate that locomotor alteration in the hSOD1G93A mouse model starts 20 days earlier than described in the literature
Summary
Amyotrophic lateral sclerosis (ALS) is a chronic neurodegenerative disease characterized by a selective degeneration of motoneurons in the motor cortex, brainstem, and spinal cord. Symptoms start with progressive weakness, atrophy of skeletal muscles and paralysis that eventually lead to death. The most extensively used SOD1G93A transgenic line harbours a mutant form of human SOD1 containing a Gly93RAla amino acid substitution [4]. These mice develop a dominantly inherited adult-onset paralytic disorder that recapitulates human ALS symptoms. Disease onset is described at around 80–90 days of age with progressive clinical weakness followed by paralysis and death by 135 days. Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by selective motoneurons degeneration. To better characterize the time course of pathological events in an animal model that recapitulates human ALS symptoms, we investigated functional and cellular characteristics of hSOD1G93A mice
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
