Figure 4.

Preclinical data suggest that providing a source of GDNF in target muscle is neuroprotective to motor circuits degenerating in ALS. In mouse models of ALS, the Sod1^G93A model being the predominant model used for these studies, neuromuscular junctions (NMJs) are denervated along with degeneration of the motor axon. The motor neuron (MN) cell body also atrophies and MNs die. The loss of innervation at NMJs causes muscle wasting and a loss of motor control that is inevitably fatal (top row). Stem cells or lentiviruses expressing Gdnf, when provided intrathecally to the spinal cord, typically support motor neuron cell bodies in the vicinity of GDNF expression. In most studies these neuroprotective effects do not travel anterogradely to maintain NMJs and do not typically improve motor function or lifespan (middle row). When sources of Gdnf are provided to muscle, such as in viral vectors or myoblasts, the NMJs generally are maintained longer, leading to longer survival of MN cell bodies and improving lifespan (bottom row). Transgenic mice engineered to express Gdnf in muscle (Myo-Gdnf) show greater neuroprotection compared to GFAP-Gdnf mice that express Gdnf in astrocytes, consistent with these other studies.