ALS: a disease of motor neurons and their nonneuronal neighbors.

Neurodegeneration in Excitotoxicity, Global Cerebral Ischemia, and Target Deprivation: A Perspective on the Contributions of Apoptosis and Necrosis

The role of neuronal growth factors in neurodegenerative disorders of the human brain

Mutations in the gene encoding copper/zinc superoxide dismutase enzyme produce an animal model of familial amyotrophic lateral sclerosis (FALS), a fatal disorder characterized by paralysis Overexpression of the proto-oncogene bcl-2 delayed onset of motor neuron disease and prolonged survival in transgenic mice expressing the FALS-linked mutation in which glycine is substituted by alanine at position 93 It did not, however, alter the duration of the disease Overexpression of bcl-2 also attenuated the magnitude of spinal cord motor neuron degeneration in the FALS-transgenic mice

https://science.sciencemag.org/content/sci/277/5325/559.full.pdf

Bcl-2: Prolonging Life in a Transgenic Mouse Model of Familial Amyotrophic Lateral Sclerosis

Molecular pathways of programmed cell death (PCD) are activated in various neurodegenerative disorders including Parkinson's disease, amyotrophic lateral sclerosis and Huntington's disease. In these diseases, PCD might be pathogenic, and targeting it might mitigate neurodegeneration. To identify potential neuroprotective targets within the PCD machinery, the expression and activity of some of its components have been altered by genetic or pharmacological means in experimental models of neurodegenerative diseases. The results of these studies have provided leads for the development of neuroprotective strategies for these progressive, disabling and often fatal disorders.

Targeting programmed cell death in neurodegenerative diseases

One of the primary neurodegenerative events occurring in amyotrophic lateral sclerosis (ALS) is the selective loss of spinal cord α motor neurons. To study the potential role of apoptosis in the degeneration of these motor neurons, in situ hybridization was used to measure the expression of two apoptotic cell death genes, bcl-2 and bax, in control and ALS lumbar spinal cord sections. The strongest hybridization signal for bcl-2 mRNA in neurological and nonneurological control spinal cords was found primarily in lamina IX α motor neurons, while a weaker hybridization signal was found in neurons of Clarke's nucleus and the proper sensory nucleus of the dorsal horn. Surviving lamina IX motor neurons in ALS spinal cord sections also expressed bcl-2 mRNA, but at levels that were significantly and selectively decreased (4.7-fold) compared with controls. bax mRNA hybridization signal was detected in several cells throughout the gray matter in control and ALS lumbar spinal cord, but was significantly and selectively increased (2.8-fold) in ALS motor neurons. Given the proposed interactive roles of these genes in apoptosis, the present findings favor a scenario in which this mode of cell death would contribute to spinal cord motor neuron degeneration in ALS.

J. He

Papers

Altered expression of bcl-2 and bax mRNA in amyotrophic lateral sclerosis spinal cord motor neurons.