Module VII. Amyotrophic lateral sclerosis, So and Yang

Module VII. Amyotrophic lateral sclerosis

Yuen So & Yanmin Yang

Neurology 205, Clinical Neuroscience, Fall Quarter, 2000-2001

The theme of this module will be the molecular pathogenesis of amyotrophic lateral sclerosis (ALS). ALS is one of the most common neurodegenerative diseases, having a prevalence of ~5 per 100,000 individuals. This disease is characterized by the selective degeneration of motor neurons and progressive muscle weakness. The precise molecular pathways that cause the death of motor neurons in ALS remain unknown. We will begin with an overview of the clinical disorder. Video vignettes will help to illustrate some of the distinctive features. We will then discuss the rather diverse clinical syndrome and the likely heterogeneity of the disease. This will lead to a discussion on the current hypotheses on molecular mechanisms and animal models of the disease. Emphasis will be placed on the toxicity of SOD1 mutations, cytoskeletal abnormalities, and recent finding of alsin gene. Following the discussion on pathogenesis, we will also discuss potential therapies that target the proposed pathogenetic mechanisms.

Papers for discussion by Michelle Monjéand Moriah Thomason:

Hadano, S., Hand, C. K., Osuga, H., Yanagisawa, Y., Otomo, A., Devon, R. S., Miyamoto, N., Showguchi-Miyata, J., Okada, Y., Singaraja, R., Figlewicz, D. A., Kwiatkowski, T., Hosler, B. A., Sagie, T., Skaug, J., Nasir, J., Brown, R. H., Jr., Scherer, S. W., Rouleau, G. A., Hayden, M. R., and Ikeda, J. E. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat.Genet. 29: 166-173, 2001.
Abstract: Amyotrophic lateral sclerosis 2 (ALS2) is an autosomal recessive form of juvenile ALS and has been mapped to human chromosome 2q33. Here we report the identification of two independent deletion mutations linked to ALS2 in the coding exons of the new gene ALS2. These deletion mutations result in frameshifts that generate premature stop codons. ALS2 is expressed in various tissues and cells, including neurons throughout the brain and spinal cord, and encodes a protein containing multiple domains that have homology to RanGEF as well as RhoGEF. Deletion mutations are predicted to cause a loss of protein function, providing strong evidence that ALS2 is the causative gene underlying this form of ALS.

Pramatarova, A., Laganiere, J., Roussel, J., Brisebois, K., and Rouleau, G. A. Neuron-specific expression of mutant superoxide dismutase 1 in transgenic mice does not lead to motor impairment. J.Neurosci. 21: 3369-3374, 2001.
Abstract: Mutations were identified in the Cu/Zn superoxide dismutase gene (SOD1) in approximately 15% of patients with familial amyotrophic lateral sclerosis. Transgenic animals expressing mutant SOD1 in all tissues develop an ALS-like phenotype. To determine whether neuron-specific expression of mutant SOD1 is sufficient to produce such a phenotype, we generated transgenic animals carrying the G37R mutation that is associated with the familial form of ALS (FALS), which is driven by the neurofilament light chain promoter. The transgenic animals express high levels of the human SOD1 protein in neuronal tissues, especially in the large motor neurons of the spinal cord, but they show no apparent motor deficit at up to 1.5 years of age. Our animal model suggests that neuron-specific expression of ALS-associated mutant human SOD1 may not be sufficient for the development of the disease in mice.