Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences

Bjartmar, Carl; Trapp, Bruce D.

doi:10.1097/00019052-200106000-00003

Cited by 431 publications

(281 citation statements)

References 56 publications

Supporting

Mentioning

262

Contrasting

Unclassified

Order By: Relevance

“…2C), and 70.0 ± 5.5% (n = 5 corpus callosa) of axonal ovoids contained detectable levels of the amyloid precursor protein (APP; Fig. 2 D-G), a marker for compromised axonal transport (3,4,35). Axonal ovoids were readily identified in EM images of corpus callosum (Fig.…”

Section: Resultsmentioning

confidence: 96%

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

Ohno

Hao

Mahad

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

View full text Add to dashboard Cite

Axonal degeneration is a primary cause of permanent neurological disability in individuals with the CNS demyelinating disease multiple sclerosis. Dysfunction of axonal mitochondria and imbalanced energy demand and supply are implicated in degeneration of chronically demyelinated axons. The purpose of this study was to define the roles of mitochondrial volume and distribution in axonal degeneration following acute CNS demyelination. We show that the axonal mitochondrial volume increase following acute demyelination of WT CNS axons does not occur in demyelinated axons deficient in syntaphilin, an axonal molecule that immobilizes stationary mitochondria to microtubules. These findings were supported by time-lapse imaging of WT and syntaphilin-deficient axons in vitro. When demyelinated, axons deficient in syntaphilin degenerate at a significantly greater rate than WT axons, and this degeneration can be rescued by reducing axonal electrical activity with the Na + channel blocker flecainide. These results support the concept that syntaphilin-mediated immobilization of mitochondria to microtubules is required for the volume increase of axonal mitochondria following acute demyelination and protects against axonal degeneration in the CNS.A xonal loss is the major cause of permanent neurological disability in individuals with primary diseases of myelin (1). Axonal degeneration associated with myelin diseases has been well studied in the immune-mediated CNS demyelinating disease multiple sclerosis. Two mechanisms are responsible for the degeneration of demyelinated axons in multiple sclerosis brains. First, axons are transected in acute multiple sclerosis lesions (2) and axonal injury correlates with the number of infiltrating peripheral immune cells (3, 4). Edema associated with breakdown of the blood-brain barrier and toxic substances secreted by inflammatory immune cells are thought to transect the acutely demyelinated axon (5). Second, chronically demyelinated axons degenerate as a result of loss of trophic support provided by oligodendrocytes and myelin (6, 7). In addition to increasing the speed of nerve transmission, oligodendrocytes and myelin provide axons with trophic support that is essential for their longterm survival (8-10). Although most demyelinated axons compensate for loss of oligodendrocytes/myelin, additional insults to axonal mitochondria impair axonal metabolism, increase axonal Ca 2+ , and promote progressive disruption of mitochondrial function (11,12). Changes in axonal mitochondria have been described in chronically demyelinated axons in postmortem multiple sclerosis tissue, and include decreased expression of nuclear-encoded mitochondrial genes (13), reduced mitochondrial respiration (14), and genetic alterations in mitochondrial DNA (15). A vicious cycle of reduced ATP production and increased axonal Ca 2+ results in degeneration of the chronically demyelinated axon.Myelinated axons contain two populations of mitochondria. Most axonal mitochondria do not appear to translocate and are located at...

show abstract

Section: Resultsmentioning

confidence: 96%

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

Ohno

Hao

Mahad

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

110

View full text Add to dashboard Cite

show abstract

“…Accordingly, by boosting a well controlled immunity that simulates or cross-reacts with weak selfreacting T cells, it is possible to counteract the destructive effect of self-compounds such as glutamate (15,19,43). Recent evidence suggests that elements of neurodegenerative and autoimmune disorders can be intermingled in the same disease Processes known to occur in degenerative diseases have been detected in autoimmune diseases (20,(44)(45)(46)(47)(48). It is thus possible that in ''mixed'' disorders the degenerative tissue will benefit from immunomodulation rather than from immunosuppression (43).…”

Section: Discussionmentioning

confidence: 99%

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

Angelov

Waibel

Guntinas‐Lichius

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

180

104

View full text Add to dashboard Cite

Therapeutic vaccination with Copaxone (glatiramer acetate, Cop-1) protects motor neurons against acute and chronic degenerative conditions. In acute degeneration after facial nerve axotomy, the number of surviving motor neurons was almost two times higher in Cop-1-vaccinated mice than in nonvaccinated mice, or in mice injected with PBS emulsified in complete Freund's adjuvant (P < 0.05). In mice that express the mutant human gene Cu͞Zn superoxide dismutase G93A (SOD1), and therefore simulate the chronic human motor neuron disease amyotrophic lateral sclerosis, Cop-1 vaccination prolonged life span compared to untreated matched controls, from 211 ؎ 7 days (n ‫؍‬ 15) to 263 ؎ 8 days (n ‫؍‬ 14; P < 0.0001). Our studies show that vaccination significantly improved motor activity. In line with the experimentally based concept of protective autoimmunity, these findings suggest that Cop-1 vaccination boosts the local immune response needed to combat destructive self-compounds associated with motor neuron death. Its differential action in CNS autoimmune diseases and neurodegenerative disorders, depending on the regimen used, allows its use as a therapy for either condition. Daily administration of Cop-1 is an approved treatment for multiple sclerosis. The protocol for non-autoimmune neurodegenerative diseases such as amyotrophic lateral sclerosis, remains to be established by future studies.

show abstract

“…14 Chronic demyelination is believed to contribute to early axonal loss and resultant progressive disability. 2,15,16 Whether or not remyelination can be achieved in chronically demyelinated lesions in multiple sclerosis remains an unanswered question. A binary, cell-specific, functional screening method identified clemastine fumarate-a first generation antihistamine-as capable of inducing oligodendrocyte differentiation and myelination due to off-target antimuscarinic effects 17 and was confirmed in a second independent screen.…”

Section: Introductionmentioning

confidence: 99%

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

et al. 2017

View full text Add to dashboard Cite

show abstract

Axonal and neuronal degeneration in multiple sclerosis: mechanisms and functional consequences

Cited by 431 publications

References 56 publications

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons

Therapeutic vaccine for acute and chronic motor neuron diseases: Implications for amyotrophic lateral sclerosis

Clemastine fumarate as a remyelinating therapy for multiple sclerosis (ReBUILD): a randomised, controlled, double-blind, crossover trial

Contact Info

Product

Resources

About