| First Author | Harrison JM | Year | 2020 |
| Journal | Neurobiol Dis | Volume | 145 |
| Pages | 105052 | PubMed ID | 32827689 |
| Mgi Jnum | J:304389 | Mgi Id | MGI:6503578 |
| Doi | 10.1016/j.nbd.2020.105052 | Citation | Harrison JM, et al. (2020) Muscle fiber-type specific terminal Schwann cell pathology leads to sprouting deficits following partial denervation in SOD1(G93A) mice. Neurobiol Dis 145:105052 |
| abstractText | Amyotrophic lateral sclerosis (ALS) is an adult-onset disease characterized by the progressive death of motoneurons and denervation of muscle fibers. To restore motor function, surviving motoneurons in partially denervated muscles typically sprout axons to reinnervate denervated endplates. However, studies on the SOD1(G93A) rodent models of ALS indicate that sprouting is significantly limited in fast, but not slow, twitch muscles after disease onset. This limitation hastens the rate of muscle weakness and loss of motor function. The causes of this limitation are currently unknown. Sprouting could be limited because the SOD1(G93A) mutation weakens motoneurons making them incapable of expanding their field of innervation. Alternatively, motoneurons may be capable of sprouting, but unable to do so due to the loss of a permissive sprouting environment. To distinguish between the two possibilities, we compared the sprouting capacity of motoneuron subtypes by partially denervating the fast twitch plantaris (composed of type IIa/IIb muscle fibers) and slow twitch soleus muscles (type I/IIa fibers) prior to disease onset and weakening in SOD1(G93A) and WT mice. We found that only motoneurons innervating the SOD1(G93A) plantaris had a limited sprouting capacity. This was correlated with the selective loss of terminal Schwann cells (TSCs) at IIb fibers and an increase in macrophage infiltration. Treating SOD1(G93A) mice with the tyrosine kinase inhibitor, masitinib, significantly reduced infiltration, prevented TSC loss, and increased the sprouting capacity to near normal. These results suggest that TSCs at denervated type IIb muscle fibers are aberrantly targeted by infiltrating macrophages in SOD1(G93A) mice, and their loss accounts, at least in part, for the compromised sprouting capacity of the largest motoneurons during early stages of ALS. |
