Neuroprotective strategies in MS: lessons from C57BL/Wld(S) mice
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Published on: September 12, 2016
Michael P Coleman1, Robert Adalbert, Bogdan Beirowski
1The Babraham Institute, Babraham, Cambridge CB2 4AT, UK. michael.coleman@bbsrc.ac.uk
Abstract:
Valuable clues about how axons degenerate in MS can be gained from axon pathology in other disorders and experimental models. We discuss the similarities in mechanism and morphology of axon pathology in diverse circumstances revealed using mutant mice. The slow Wallerian degeneration mutation, Wld(S), delays three types of axon degeneration previously considered distinct: Wallerian degeneration of injured axons, 'dying-back' of axons in peripheral nervous system disease, and axonal spheroid pathology in gracile axonal dystrophy (gad) mice. Therefore, axon degeneration mechanisms are more uniform than previously thought and, in gad at least, axonal swelling is either related to or a consequence of Wallerian degeneration. Both axonal swelling and the accumulation of amyloid precursor protein through impaired axonal transport are common to MS, gad, and many other CNS disorders, indicating a degree of shared mechanism. YFP-H transgenic mice express YFP in a representative subset of neurons enabling unprecedented imaging of axon morphology and pathology over considerable longitudinal distances. Using this method, we have observed unbroken axons with multiple constrictions and dilatations in VEGF(delta/delta) mice, a model of amyotrophic lateral sclerosis (ALS). Similar morphologies have been described in MS, stroke, and other disorders, again suggesting a uniformity of axon degeneration mechanisms.
Insights
Axon degeneration mechanisms in multiple sclerosis (MS) and other neurological disorders share common pathways. Studies reveal that axonal swelling and impaired transport are key features, suggesting uniform degeneration processes across diseases.
Area of Science:
- Neuroscience
- Cell Biology
- Pathology
Background:
- Axon degeneration is a hallmark of multiple sclerosis (MS) and other central nervous system (CNS) disorders.
- Understanding shared mechanisms of axon pathology across different diseases can provide insights into MS pathogenesis.
Purpose of the Study:
- To investigate the commonalities in axon degeneration mechanisms and morphology across various neurological conditions.
- To explore whether distinct forms of axon degeneration share underlying molecular pathways.
Main Methods:
- Comparative analysis of axon pathology in mutant mouse models, including slow Wallerian degeneration (Wld(S)) and gracile axonal dystrophy (gad) mice.
- Utilizing YFP-H transgenic mice for longitudinal imaging of axon morphology and pathology.
- Examining axonal spheroid pathology and axonal swelling in disease models.
Main Results:
- The slow Wallerian degeneration (Wld(S)) mutation delays three previously distinct types of axon degeneration, suggesting a unified mechanism.
- Axonal swelling in gracile axonal dystrophy (gad) mice is linked to or a consequence of Wallerian degeneration.
- Impaired axonal transport, leading to amyloid precursor protein accumulation and axonal swelling, is common to MS, gad, and other CNS disorders.
- Imaging revealed axons with constrictions and dilatations in amyotrophic lateral sclerosis (ALS) models, similar to morphologies observed in MS and stroke.
Conclusions:
- Axon degeneration mechanisms are more uniform across different neurological disorders than previously assumed.
- Shared pathways, including axonal swelling and impaired axonal transport, are implicated in the pathogenesis of MS, gad, ALS, and other CNS conditions.
- Further research into these common mechanisms could reveal novel therapeutic targets for neurodegenerative diseases.
