Novel therapeutical targets for ALS: neuregulin and sigma receptor complex
Institute of Neurosciences (INc), Autonomous University of Barcelona
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive weakness, muscle atrophy and paralysis due to the loss of upper and lower motoneurons. Studies using animal models have demonstrated that ALS pathogenesis would be the result of glutamate excitotoxicity, oxidative stress, protein misfolding, mitochondrial defects, impaired axonal transport, and inflammation, all these factors contributing to motoneuron death. Given the complexity of its etiopathogenesis, treatments targeting different mechanisms in combination are likely needed to achieve relevant beneficial effects.
The Sigma-1 receptor, highly expressed in motoneurons, mediates regulation of several processes, such as neuritogenesis, excitability, NMDA receptors activity, Ca2+ homeostasis, and microglial activity.
Administration of the Sigma-1R agonist, PRE-084, in the SOD1G93A mouse model of ALS produced significant improvement in electrophysiological and locomotor tests, and preservation of neuromuscular connections and motoneurons in the spinal cord. Moreover, it extended survival in both female and male transgenic mice by more than 15%.
Neuregulin-1 (Nrg1) is a neurotrophic factor essential for the development and maintenance of neuromuscular junctions. We overexpressed Nrg1 type I by means of an adeno-associated viral (AAV) vector in SOD1G93A mice muscles, and found that such intramuscular administration promoted motor axon collateral sprouting by acting on terminal Schwann cells, preventing denervation of the injected muscles through Akt and ERK1/2 pathways. These results demonstrate that Nrg1-I plays a crucial role in collateral reinnervation, opening a window for developing novel ALS therapies for functional recovery rather than preservation.
Nrg1 type III is highly expressed in MNs, at the postsynaptic space of C buttons, where it is linked to Sigma-1R. To explore the central effects of Nrg1, we intrathecally injected an AVV to overexpress Nrg1-III in the spinal cord of SOD1G93A mice, and found that it promoted significant improvement in the motor function and the survival of motoneurons.
All these results point to the Nrg1 and Sigma-1R as promising candidates for a combinatory therapeutical strategy of ALS.
Host: Alberto Pérez Samartín