Axon guidance proteins: novel therapeutic targets for ALS?

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disease characterized by the selective loss of motor neurons in the brain and spinal cord. Death due to respiratory failure occurs typically 2-5 years after disease onset. The pathogenic mechanism that underlies ALS remains largely unknown, but is known to include both genetic and environmental factors. At the cellular level, pathological changes in motor neuron connections and loss of neuromuscular contacts precede motor neuron degeneration and clinical symptoms. Several lines of recent evidence support the challenging hypothesis that aberrant expression or function of axon guidance proteins such as Semaphorins, Ephrins, Netrins and Slits, normally involved in sculpting and maintaining motor neuron circuits, may induce such pathological changes in motor neuron circuitry and contribute to the pathogenic mechanism involved in ALS. In the present review, we discuss the emerging roles of axon guidance proteins in the pathogenesis of ALS. First, we summarize our current understanding of the role of axon guidance proteins during the formation of motor neuron circuits. Subsequently, we present several lines of evidence showing an association between aberrant axon guidance protein function or expression and ALS. Finally, we discuss the therapeutic potential of axon guidance proteins in understanding and treating the changes in motor neuron connectivity that underlie this debilitating disease.