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Clinical Testing and Spinal Cord Removal in a Mouse Model for Amyotrophic Lateral Sclerosis ALS
Published on: March 17, 2012
ADAMTS-4 promotes neurodegeneration in a mouse model of amyotrophic lateral sclerosis
Sighild Lemarchant1, Yuriy Pomeshchik2, Iurii Kidin3
1Department of Neurobiology, A. I. Virtanen Institute for Molecular Sciences, Biocenter Kuopio, University of Eastern Finland, P.O. Box 1627, 70211, Kuopio, Finland. sighild.lemarchant@uef.fi.
Background:
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. Therefore, we investigated the expression, effects and associated mechanisms of ADAMTS-4 during amyotrophic lateral sclerosis (ALS) in the SOD1(G93A) mouse model.
Results:
ADAMTS-4 expression and activity were reduced in the spinal cord of SOD1(G93A) mice at disease end-stage when compared to WT littermates. To counteract the loss of ADAMTS-4, SOD1(G93A) and WT mice were treated with saline or a recombinant ADAMTS-4 before symptom onset. Administration of ADAMTS-4 worsened the prognosis of SOD1(G93A) mice by accelerating clinical signs of neuromuscular dysfunctions. The worsened prognosis of ADAMTS-4-treated SOD1(G93A) 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 SOD1(G93A) 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.
Conclusions:
This 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.
Insights
Reduced ADAMTS-4 activity in amyotrophic lateral sclerosis (ALS) may protect neurons. Supplementing ADAMTS-4 worsened disease in a mouse model, indicating therapies targeting this enzyme are unlikely to treat ALS.
Area of Science:
- Neuroscience
- Biochemistry
- Molecular Biology
Background:
- A disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) proteoglycanases degrade chondroitin sulfate proteoglycans and influence neuroplasticity.
- While ADAMTS-4 aids neurorepair after spinal cord injury, its role in other central nervous system (CNS) diseases remains unexplored.
- This study investigates ADAMTS-4 in amyotrophic lateral sclerosis (ALS) using the SOD1(G93A) mouse model.
Purpose of the Study:
- To examine ADAMTS-4 expression and activity in the SOD1(G93A) mouse model of ALS.
- To determine the effects of exogenous ADAMTS-4 administration on ALS progression.
- To elucidate the mechanisms underlying ADAMTS-4's impact on motoneuron survival.
Main Methods:
- Assessed ADAMTS-4 expression and activity in spinal cords of SOD1(G93A) and wild-type (WT) mice.
- Administered recombinant ADAMTS-4 to SOD1(G93A) and WT mice before symptom onset.
- Evaluated clinical signs, motoneuron degeneration, perineuronal net integrity, and neurotrophic factor production.
Main Results:
- ADAMTS-4 expression and activity were decreased in SOD1(G93A) mice at end-stage disease.
- ADAMTS-4 administration accelerated disease progression and neuromuscular dysfunction in SOD1(G93A) mice.
- Treatment increased perineuronal net degradation and motoneuron loss, likely due to extracellular matrix disruption and reduced neurotrophic factors.
Conclusions:
- Reduced ADAMTS-4 activity during ALS progression may be a compensatory mechanism to limit neurodegeneration.
- Therapeutic strategies aimed at increasing ADAMTS-4 activity are unlikely to be beneficial for ALS treatment.
