Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive death of cortical and spinal motor neurons, for which there is no effective treatment. Using a cell-based assay for compounds capable of preventing motor neuron cell death in vitro, a collection of approximately 40,000 low-molecular-weight compounds was screened to identify potential small-molecule therapeutics. We report the identification of cholest-4-en-3-one, oxime (TRO19622) as a potential drug candidate for the treatment of ALS. In vitro, TRO19622 promoted motor neuron survival in the absence of trophic support in a dose-dependent manner. In vivo, TRO19622 rescued motor neurons from axotomy-induced cell death in neonatal rats and promoted nerve regeneration following sciatic nerve crush in mice. In SOD1G93A transgenic mice, a model of familial ALS, TRO19622 treatment improved motor performance, delayed the onset of the clinical disease, and extended survival. TRO19622 bound directly to two components of the mitochondrial permeability transition pore: the voltage-dependent anion channel and the translocator protein 18 kDa (or peripheral benzodiazepine receptor), suggesting a potential mechanism for its neuroprotective activity. TRO19622 may have therapeutic potential for ALS and other motor neuron and neurodegenerative diseases.Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder that selectively affects motor neurons in the spinal cord, brainstem, and cortex. ALS affects people of all races and ethnic backgrounds with an incidence approximately 2 per 100,000 individuals (McGuire and Nelson, 2006). The onset of ALS is most common in the 55 to 75 year age range, and incidence rises with advancing age; men have a higher risk of developing the disease than women (Nelson, 1995). Common clinical features of ALS include muscle weakness and fasciculations. These occur predominantly in limbs, although bulbar onset pathology can also lead to tongue atrophy and dysphagia. Failure of the respiratory muscles and cardiac complications are generally the fatal event, occurring within an average of 3 years of disease onset, with only a 5% chance of survival 5 years after diagnosis (del Aguila et al., 2003). Although 5 to 10% of ALS This work was supported by the Association Française contre les Myopathies.1 Current affiliation: Center for Motor Neuron Biology and Disease, Columbia University, New York.Article, publication date, and citation information can be found at
