| First Author | Spiller KJ | Year | 2019 |
| Journal | Neurobiol Dis | Volume | 124 |
| Pages | 133-140 | PubMed ID | 30458231 |
| Mgi Jnum | J:277913 | Mgi Id | MGI:6295742 |
| Doi | 10.1016/j.nbd.2018.11.013 | Citation | Spiller KJ, et al. (2019) Reduction of matrix metalloproteinase 9 (MMP-9) protects motor neurons from TDP-43-triggered death in rNLS8 mice. Neurobiol Dis 124:133-140 |
| abstractText | Therapeutic strategies are needed for the treatment of amyotrophic lateral sclerosis (ALS). One potential target is matrix metalloproteinase-9 (MMP-9), which is expressed only by fast motor neurons (MNs) that are selectively vulnerable to various ALS-relevant triggers. Previous studies have shown that reduction of MMP-9 function delayed motor dysfunction in a mouse model of familial ALS. However, given that the majority of ALS cases are sporadic, we propose preclinical testing in a mouse model which may be more clinically translatable: rNLS8 mice. In rNLS8 mice, neurodegeneration is triggered by the major pathological hallmark of ALS, TDP-43 mislocalization and aggregation. MMP-9 was targeted in 3 different ways in rNLS8 mice: by AAV9-mediated knockdown, using antisense oligonucleotide (ASO) technology, and by genetic modification. All 3 strategies preserved the motor unit during disease, as measured by MN counts, tibialis anterior (TA) muscle innervation, and physiological recordings from muscle. However, the strategies that reduced MMP-9 beyond the motor unit lead to premature deaths in a subset of rNLS8 mice. Therefore, selective targeting of MMP-9 in MNs could be beneficial in ALS, but side effects outside of the motor circuit may limit the most commonly used clinical targeting strategies. |
