Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part II, results and discussion.

Pathological events are well characterized in amyotrophic lateral sclerosis (ALS) mouse models, but review of the literature fails to identify a specific initiating event that precipitates disease pathology. There is now growing consensus in the field that axon and synapses are first cellular sites of degeneration, but controversy exists over whether axon and synapse loss is initiated autonomously at those sites or by pathology in the cell body, in nonneuronal cells or even in nonmotoneurons (MNs). Previous studies have identified pathological events in the mutant superoxide dismutase 1 (SOD1) models involving spinal cord, peripheral axons, neuromuscular junctions (NMJs), or muscle; however, few studies have systematically examined pathogenesis at multiple sites in the same study.

Characterization of early pathogenesis in the SOD1(G93A) mouse model of ALS: part I, background and methods.

Charcot first described amyotrophic lateral sclerosis (ALS) in 1869; however, its causes remain largely unknown and effective, long-term treatment strategies are not available. The first mouse model of ALS was developed after the identification of mutations in the superoxide dismutase 1 (SOD1) gene in 1993, and accordingly most of our knowledge of the etiology and pathogenesis of the disease comes from studies carried out using this animal model. Although numerous preclinical trials have been conducted in the mutant SOD1 mouse models, the results have been disappointing because they did not positively translate to clinical trials.

Misplacement of Purkinje cells during postnatal development in Bax knock-out mice: a novel role for programmed cell death in the nervous system?

During early postnatal development, the orchestrated regulation of proliferation, migration and the survival versus elimination of neurons is essential for histogenesis of the cerebellum. For instance, Purkinje cells (PCs) promote the proliferation and migration of external granule cells (EGCs), whereas EGCs in turn play a role in the migration of PCs. Considering that a substantial number of neurons undergo programmed cell death (PCD) during cerebellar development, it seems likely that neuronal loss could have a significant role in the histogenesis of the cerebellum.

Developing postmitotic mammalian neurons in vivo lacking Apaf-1 undergo programmed cell death by a caspase-independent, nonapoptotic pathway involving autophagy.

Previous studies have shown that caspases and Apaf-1 are required for the normal programmed cell death (PCD) in vivo of immature postmitotic neurons and mitotically active neuronal precursor cells. In contrast, caspase activity is not necessary for the normal PCD of more mature postmitotic neurons that are establishing synaptic connections. Although normally these cells use caspases for PCD, in the absence of caspase activity these neurons undergo a distinct nonapoptotic type of degeneration.

Impaired migration in the rostral migratory stream but spared olfactory function after the elimination of programmed cell death in Bax knock-out mice.

Rats and mice exhibit neurogenesis of olfactory bulb (OB) interneurons throughout adulthood. To homeostatically maintain stable neuron numbers, it is necessary to continuously remove a subset of OB neurons by programmed cell death (PCD). Here we demonstrate that Bax is critical for the elimination of OB neurons by showing that Bax-KO mice exhibit greatly reduced PCD in the OB.

Neuromuscular development in the absence of programmed cell death: phenotypic alteration of motoneurons and muscle.

The widespread, massive loss of developing neurons in the central and peripheral nervous system of birds and mammals is generally considered to be an evolutionary adaptation. However, until recently, models for testing both the immediate and long-term consequences of preventing this normal cell loss have not been available. We have taken advantage of several methods for preventing neuronal death in vivo to ask whether rescued neurons [e.

Discoordinate regulation of renal nitric oxide synthase isoforms in ovariectomized mRen2. Lewis rats.

Estrogen depletion markedly exacerbates hypertension in female congenic mRen2. Lewis rats, a model of tissue renin overexpression. Because estrogen influences nitric oxide synthase (NOS) and NO may exert differential effects on blood pressure, the present study investigated the functional expression of NOS isoforms in the kidney of ovariectomized (OVX) mRen2.

Complete dissociation of motor neuron death from motor dysfunction by Bax deletion in a mouse model of ALS.

The death of cranial and spinal motoneurons (MNs) is believed to be an essential component of the pathogenesis of amyotrophic lateral sclerosis (ALS). We tested this hypothesis by crossing Bax-deficient mice with mice expressing mutant superoxide dismutase 1 (SOD1), a transgenic model of familial ALS. Although Bax deletion failed to prevent neuromuscular denervation and mitochondrial vacuolization, MNs were completely rescued from mutant SOD1-mediated death.

Programmed cell death of adult-generated hippocampal neurons is mediated by the proapoptotic gene Bax.

In the dentate gyrus (DG) of the adult mouse hippocampus, a substantial number of new cells are generated daily, but only a subset of these survive and differentiate into mature neurons, whereas the majority undergo programmed cell death (PCD). However, neither the intracellular machinery required for adult stem cell-derived neuronal death nor the biological implications of the significant loss of these newly generated cells have been examined. Several markers for apoptosis failed to reveal cell death in Bax-deficient mice, and this, together with a progressive increase in neuron number in the DG of the Bax knock-out, indicates that Bax is critical for the PCD of adult-generated hippocampal neurons.

Neuromuscular development after the prevention of naturally occurring neuronal death by Bax deletion.

The removal of excess neurons by programmed cell death (PCD) is believed to be critical for the proper development and function of the nervous system. A major role of this neuronal loss is to attain quantitative matching of neurons with their targets and afferents. Because motoneurons (MNs) in Bax knock-out (Bax KO) mice fail to undergo PCD in the face of normal target muscle development, we asked whether the excess rescued neurons in Bax KO mice can develop normally.

Differential expression of the GDNF family receptors RET and GFRalpha1, 2, and 4 in subsets of motoneurons: a relationship between motoneuron birthdate and receptor expression.

Previous studies have demonstrated the expression of specific members of the glial cell line-derived neurotrophic factor (GDNF) receptor family alpha (GFRalpha) in subsets of motoneurons (MNs) in the developing mouse spinal cord. We examined the expression pattern of GFRalpha and RET in the avian lumbar spinal cord during the period of programmed cell death (PCD) of MNs by using double labeling in situ hybridization and immunohistochemistry. In the lateral motor column (LMC) of the lumbar spinal cord, a laminar organization of GFRalpha expression was observed: GFRalpha1-positive MNs were located in the medial LMC; GFRalpha1-, 2-, and 4-positive MNs were situated in the lateral LMC; and GFRalpha4-positive MNs were located in the intermediate LMC.