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

Abstract

One of the primary neurodegenerative events occurring in amyotrophic lateral sclerosis (ALS) is the selective loss of spinal cord alpha 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 alpha 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.

Cell Cycle Regulators in the Neuronal Death Pathway of Amyotrophic Lateral Sclerosis Caused by Mutant Superoxide Dismutase 1

“…There is evidence that alterations in levels of Bax, Bcl-2, and Bcl-x proteins may also contribute to neurodegeneration in mutant SOD1 mice and in ALS patients (Mu et al, 1996, Ekegren et al, 1999Martin, 1999;Vukosavic et al, 1999;Gonzalez de Aguilar et al, 2000). The overexpression of Bcl-2 in SOD1 G93A mice delayed caspase-3 activation, indicating that insults leading to an unbalanced ratio of Bcl-2 family members might promote death signals (Kostic et al, 1997;Pasinelli et al, 1998Pasinelli et al, , 2000Li et al, 2000;Vukosavic et al, 2000).…”

Characterization of MPP+-Induced Cell Death in a Dopaminergic Neuronal Cell Line: Role of Macromolecule Synthesis, Cytosolic Calcium, Caspase, and Bcl-2-Related Proteins

“…In addition, upregulation of Bax expression has been demonstrated in the neurons of a patient with neurodegenerative disorders and of an experimental animal model (13,21,27,38). However, the level of Bax is not upregulated during the course of MPP ϩ -induced cell death in MN9D cells.…”

Proapoptotic multidomain Bcl-2/Bax-family proteins: mechanisms, physiological roles, and therapeutic opportunities

“…Increased Bax expression also has been observed in spinal motoneurons in patients with Amyotrophic Lateral Sclerosis (ALS). 37 Moreover, in transgenic mutant SOD1 mice (a model of ALS), Bax protein activation has been detected. 38 Marked elevations in Bax protein levels have been reported in microglial cells and astrocytes in association with apoptosis in patients with HIV-induced encephalitis.…”