Abstract
BackgroundA disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteoglycanases are specialized in the degradation of chondroitin sulfate proteoglycans and participate in mechanisms mediating neuroplasticity. Despite the beneficial effect of ADAMTS-4 on neurorepair after spinal cord injury, the functions of ADAMTS proteoglycanases in other CNS disease states have not been studied. Therefore, we investigated the expression, effects and associated mechanisms of ADAMTS-4 during amyotrophic lateral sclerosis (ALS) in the SOD1G93A mouse model.ResultsADAMTS-4 expression and activity were reduced in the spinal cord of SOD1G93A mice at disease end-stage when compared to WT littermates. To counteract the loss of ADAMTS-4, SOD1G93A and WT mice were treated with saline or a recombinant ADAMTS-4 before symptom onset. Administration of ADAMTS-4 worsened the prognosis of SOD1G93A mice by accelerating clinical signs of neuromuscular dysfunctions. The worsened prognosis of ADAMTS-4-treated SOD1G93A mice was accompanied by increased degradation of perineuronal nets enwrapping motoneurons and increased motoneuron degeneration in the lumbar spinal cord. Motoneurons of ADAMTS-4-treated SOD1G93A mice were more vulnerable to degeneration most likely due to the loss of their extracellular matrix envelopes. The decrease of neurotrophic factor production induced by ADAMTS-4 in vitro and in vivo may also contribute to a hostile environment for motoneuron especially when devoid of a net.ConclusionsThis study suggests that the reduction of ADAMTS-4 activity during the progression of ALS pathology may be an adaptive change to mitigate its neurodegenerative impact in CNS tissues. Therapies compensating the compromized ADAMTS-4 activity are likely not promising approaches for treating ALS.
Highlights
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteoglycanases are specialized in the degradation of chondroitin sulfate proteoglycans and participate in mechanisms mediating neuroplasticity
ADAMTS-4 mRNA levels were considerably decreased in SOD1G93A male mice compared to WT at the symptomatic and endstages of the disease (Fig. 2a: −53.7 % at symptomatic stage (SS), −85.7 % at end stage (ES) compared to age-matched WT, P = 0.0209)
Contrary to ADAMTS-4, ADAMTS-1 (Fig. 2b: +92.1 % at SS, +410.7 % at ES compared to age-matched WT, P = 0.0433, P = 0.0209, respectively), ADAMTS-5 (Fig. 2c: +148.9 % at ES compared to age-matched WT, P = 0.0339) and ADAMTS-9 (Fig. 2d: +149.6 % at ES compared to age-matched WT, P = 0.0209) mRNA levels were significantly increased in the lumbar spinal cord of SOD1G93A male mice compared to WT at the symptomatic and/or end-stages of the disease
Summary
A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteoglycanases are specialized in the degradation of chondroitin sulfate proteoglycans and participate in mechanisms mediating neuroplasticity. Despite the beneficial effect of ADAMTS-4 on neurorepair after spinal cord injury, the functions of ADAMTS proteoglycanases in other CNS disease states have not been studied. The worsened prognosis of ADAMTS-4treated SOD1G93A mice was accompanied by increased degradation of perineuronal nets enwrapping motoneurons and increased motoneuron degeneration in the lumbar spinal cord. While deregulated expression of ADAMTS proteoglycanases has been previously reported during acute CNS injuries, such as stroke [7,8,9] and spinal cord injury [5, 6, 10], the Lemarchant et al Molecular Neurodegeneration (2016) 11:10 expression and function of ADAMTS proteoglycanases have not been studied in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS). It is essential to further understand mechanisms underlying ALS development in order to find new approaches for diagnostics and therapy
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