Involvement of neuronal and muscular Trk-fused gene (TFG) defects in the development of neurodegenerative diseases

Abstract

Trk-fused gene (TFG) mutations have been identified in patients with several neurodegenerative diseases. In this study, we attempted to clarify the effects of TFG deletions in motor neurons and in muscle fibers, using tissue-specific TFG knockout (vMNTFG KO and MUSTFG KO) mice. vMNTFG KO, generated by crossing TFG floxed with VAChT-Cre, showed deterioration of motor function and muscle atrophy especially in slow-twitch soleus muscle, in line with the predominant Cre expression in slow-twitch fatigue-resistant (S) and fast-twitch fatigue-resistant (FR) motor neurons. Consistently, denervation of the neuromuscular junction (NMJ) was apparent in the soleus, but not in the extensor digitorum longus, muscle. Muscle TFG expressions were significantly downregulated in vMNTFG KO, presumably due to decreased muscle IGF-1 concentrations. However, interestingly, MUSTFG KO mice showed no apparent impairment of muscle movements, though a denervation marker, AChRγ, was elevated and Agrin-induced AChR clustering in C2C12 myotubes was inhibited. Our results clarify that loss of motor neuron TFG is sufficient for the occurrence of NMJ degeneration and muscle atrophy, though lack of muscle TFG may exert an additional effect. Reduced muscle TFG, also observed in aged mice, might be involved in age-related NMJ degeneration, and this issue merits further study.

TFG regulates secretory and endosomal sorting pathways in neurons to promote their activity and maintenance

“…The irregular firing pattern identified in the homozygous mutant animals suggested muscle fasciculation consistent with decreased inhibition of motor neurons, as opposed to muscle denervation. These findings contrast the effect of deleting TFG in motor neurons, which results in denervation of neuromuscular junctions ( 47 ), strongly suggesting that the p.R106C mutation only partially reduced TFG function. Notably, neither control nor heterozygous TFG p.R106C mutant animals showed similar signs of muscle spasticity, consistent with the point mutation acting recessively ( Fig.…”

A novel TFG variant of uncertain significance in amyotrophic lateral sclerosis: A case report and review of literature

“…TFG is also an inhibitory regulator of ubiquitin-proteasome system (UPS). And this is responsible for unfolded protein response (UPR), which finally results in cell death [ 15 , 17 ]. This suggests that the mutation in TFG results in disruption of intracellular protein homeostasis in nervous system too [ [18] , [19] , [20] ].…”