Modelling a Novel Superoxide Dismutase 1 Mutation in Motor Neurons: An Insight into Molecular Pathomechanism of Amyotrophic Lateral Sclerosis

Glia cells are involved in upper motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Protease activated receptor 1 (PAR1) pathway is related to brain pathologies. Brain PAR1 is located on peri-synaptic astrocytes, adjacent to pyramidal motor neurons, suggesting possible involvement in ALS. Brain thrombin activity in superoxide dismutase 1 (SOD1) mice was measured using a fluorometric assay, and PAR1 levels by western blot. PAR1 was localized using immunohistochemistry staining. Treatment targeted PAR1 pathway on three levels; thrombin inhibitor TLCK (N-Tosyl-Lys-chloromethylketone), PAR1 antagonist SCH-79797 and the Ras intracellular inhibitor FTS (S-trans-trans-farnesylthiosalicylic acid). Mice were weighed and assessed for motor function and survival. SOD1 brain thrombin activity was increased (p < 0.001) particularly in the posterior frontal lobe (p = 0.027) and hindbrain (p < 0.01). PAR1 levels were decreased (p < 0.001, brain, spinal cord, p < 0.05). PAR1 and glial fibrillary acidic protein (GFAP) staining decreased in the cerebellum and cortex. SOD1 mice lost weight (≥17 weeks, p = 0.047), and showed shorter rotarod time (≥14 weeks, p < 0.01). FTS 40mg/kg significantly improved rotarod scores (p < 0.001). Survival improved with all treatments (p < 0.01 for all treatments). PAR1 antagonism was the most efficient, with a median survival improvement of 10 days (p < 0.0001). Our results support PAR1 pathway involvement in ALS.

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Absence of neurofilaments reduces the selective vulnerability of motor neurons and slows disease caused by a familial amyotrophic lateral sclerosis-linked superoxide dismutase 1 mutant

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.95.16.9631 ◽

1998 ◽

Vol 95 (16) ◽

pp. 9631-9636 ◽

Cited By ~ 137

Author(s):

Toni L. Williamson ◽

Lucie I. Bruijn ◽

Qinzhang Zhu ◽

Karen L. Anderson ◽

Scott D. Anderson ◽

...

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Superoxide Dismutase ◽

Motor Neurons ◽

Selective Vulnerability ◽

Superoxide Dismutase 1 ◽

Filament Assembly ◽

Progression Of Disease ◽

Familial Als ◽

Sod1 Mutant ◽

Lateral Sclerosis

Mutations in superoxide dismutase 1 (SOD1), the only proven cause of amyotrophic lateral sclerosis (ALS), provoke disease through an unidentified toxic property. Neurofilament aggregates are pathologic hallmarks of both sporadic and SOD1-mediated familial ALS. By deleting NF-L, the major neurofilament subunit required for filament assembly, onset and progression of disease caused by familial ALS-linked SOD1 mutant G85R are significantly slowed, while selectivity of mutant-mediated toxicity for motor neurons is reduced. In NF-L-deleted animals, levels of the two remaining neurofilament subunits, NF-M and NF-H, are markedly reduced in axons but are elevated in motor neuron cell bodies. Thus, while neither perikaryal nor axonal neurofilaments are essential for SOD1-mediated disease, the absence of assembled neurofilaments both diminishes selective vulnerability and slows SOD1G85R mutant-mediated toxicity to motor neurons.

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