NMDA and non-NMDA receptor-mediated differential Ca2+ load and greater vulnerability of motor neurons in spinal cord cultures

Glutamate receptor activated neuronal cell death has been implicated in the pathogenesis of motor neuron disease but the molecular mechanism responsible for neuronal dysfunction needs to be elucidated. In the present study, we examined the contribution of NMDA and non-NMDA sub-types of glutamate receptors in selective vulnerability of motor neurons. Glutamate receptor activated Ca2+ signaling, mitochondrial functions and neurotoxicity in motor neurons and other spinal neurons were studied in mixed spinal cord primary cultures. Exposure of cells to glutamate receptor agonists glutamate, NMDA and AMPA elevated the intracellular Ca2+, mitochondrial Ca2+ and caused mitochondrial depolarization and cytotoxicity in both motor neurons and other spinal neurons but a striking difference was observed in the magnitude and temporal patterns of the [Ca2+]i responses between the two neuronal cell types. The motor neurons elicited higher Ca2+ load than the other spinal neurons and the [Ca2+]i levels were elevated for a longer duration in motor neurons. AMPA receptor stimulation was more effective than NMDA. Both the NMDA and non-NMDA receptor antagonists APV and NBQX inhibited the Ca2+ entry and decreased the cell death significantly; however, NBQX was more potent than APV. Our results demonstrate that both NMDA and non-NMDA sub-types of glutamate receptors contribute to glutamate-mediated motor neuron damage but AMPA receptors play the major role. AMPA receptor-mediated excessive Ca2+ load and differential handling/regulation of Ca2+ buffering by mitochondria in motor neurons could be central in their selective vulnerability to excitotoxicity.     

Astrocytes in amyotrophic lateral sclerosis: direct effects on motor neuron survival

Selective motor neuron death during amyotrophic lateral sclerosis (ALS) is a non-cell autonomous process in which non-neuronal cells induce and/or contribute to the disease process. The non-neuronal cells that are clearly involved in the pathogenesis of the disease are the surrounding astrocytes. Under normal conditions, astrocytes remove glutamate from the synaptic cleft and release trophic factors. In addition, these cells determine the functional characteristics of motor neurons. Recent evidence suggests that activation of astrocytes in a degenerative disease like ALS disturbs the crosstalk between astrocytes and motor neurons, which could contribute to and/or accelerate selective motor neuron death. These new insights may contribute to the development of therapeutic approaches to slow this fatal neurodegenerative disease.     

Molecular mechanisms of calcium-dependent neurodegeneration in excitotoxicity

Excitotoxicity contributes to neuronal degeneration in many acute CNS diseases, including ischemia, trauma, and epilepsy, and may also play a role in chronic diseases, such as amyotrophic lateral sclerosis (ALS). Key mediators of excitotoxic damage are Ca ions (Ca(2+)), which under physiological conditions govern a multitude of cellular processes, including cell growth, differentiation, and synaptic activity. Consequently, homeostatic mechanisms exist to maintain a low intracellular Ca(2+) ion concentration so that Ca(2+) signals remain spatially and temporally localized. This permits multiple independent Ca-mediated signaling pathways to occur in the same cell. In excitotoxicity, excessive synaptic release of glutamate can lead to the disregulation of Ca(2+) homeostasis. Glutamate activates postsynaptic receptors, including the ionotropic N-methyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) proprionate (AMPA), and kainate receptors. Upon their activation, these open their associated ion channel to allow the influx of Ca(2+) and Na(+) ions. Although physiological elevations in intracellular Ca(2+) are salient to normal cell functioning, the excessive influx of Ca(2+) together with any Ca(2+) release from intracellular compartments can overwhelm Ca(2+)-regulatory mechanisms and lead to cell death. Although Ca(2+) disregulation is paramount to neurodegeneration, the exact mechanism by which Ca(2+) ions actually mediate excitotoxicity is less clear. One hypothesis outlined in this review suggests that Ca(2+)-dependent neurotoxicity occurs following the activation of distinct signaling cascades downstream from key points of Ca(2+) entry at synapses, and that triggers of these cascades are physically co-localized with specific glutamate receptors. Thus, we summarize the importance of Ca(2+) regulation in mammalian neurons and the excitotoxicity hypothesis, and focus on the molecular determinants of glutamate receptor-mediated excitotoxic mechanisms.     

Role of mitochondria in kainate-induced fast Ca2+ transients in cultured spinal motor neurons

Motor neuron death in amyotrophic lateral sclerosis (ALS) has been linked to selective vulnerability towards AMPA receptor-mediated excitotoxicity. We investigated intracellular mechanisms leading to impairment of motor neuron Ca2+ homeostasis with near physiological AMPA receptor activation. Using fast solution exchange on patch-clamped cultured neurons, kainate (KA) was applied for 2s. This induced a transient increase in the cytosolic Ca2+ concentration ([Ca2+]c) for seconds. Inhibition of the mitochondrial uniporter by RU-360 abolished the decay of the Ca2+ transient and caused immediate [Ca2+]c overload. Repetitive short KA stimulation caused a slowing of the decay of the Ca2+ transient and a gradual increase in peak and baseline [Ca2+]c in motor neurons, but not in other neurons, indicating saturation of the mitochondrial buffer. Furthermore, mitochondrial density was lower in motor neurons and, in a network of neurons with physiological synaptic AMPA receptor input, RU-360 acutely induced an increase in Ca2+ transients. We conclude that motor neurons have an insufficient mitochondrial capacity to buffer large Ca2+ elevations which is partly due to a reduced mitochondrial density per volume compared to non-motor neurons. This may exert deleterious effects in motor neuron disease where mitochondrial function is thought to be compromised.     

谷氨酸转运抑制剂对器官型培养脊髓片的影响

观察谷氨酸转运体抑制剂苏一羟天冬氨酸(Threo-hydroxyaspartate,THA)对器官型培养的脊髓片的影响,探讨谷氨酸在运动神经元损伤中的作用。取出生后8天乳鼠的腰段脊髓组织切片做脊髓器官型培养,在培养液中加入不同浓度THA(50μmol／L、100μmol／L、5001μmol／L),用神经元的特异性免疫组化染色剂SMI-32,非磷酸化神经丝标记物,对脊髓腹角α运动神经元进行鉴定,用单克隆抗钙网膜蛋白(calretinin)抗体对背角中间神经元进行记数,测定培养液中乳酸脱氢酶(LDH)的含量,并与对照组比较。结果显示对照组α运动神经元数目恒定,THA可以引起剂量依赖性的培养液中LDH含量增高和α运动神经元数目减少,而脊髓背角的中间神经元损伤相对较轻,其中THA100μmol／L组在体外培养4周后出现类似于肌萎缩侧索硬化(ALS)的病理改变：α运动神经元数目较对照组明显减少,而脊髓背角的中间神经元数目无显著变化。细胞外谷氨酸增高主要对运动神经元造成损伤,脊髓运动神经元较感觉神经元对谷氨酸的兴奋毒作用更加敏感。     

Identifying the primary site of pathogenesis in amyotrophic lateral sclerosis – vulnerability of lower motor neurons to proximal excitotoxicity

There is a desperate need for targeted therapeutic interventions that slow the progression of amyotrophic lateral sclerosis (ALS). ALS is a disorder with heterogeneous onset, which then leads to common final pathways involving multiple neuronal compartments that span both the central and peripheral nervous system. It is believed that excitotoxic mechanisms might play an important role in motor neuron death in ALS. However, little is known about the mechanisms by which excitotoxicity might lead to the neuromuscular junction degeneration that characterizes ALS, or about the site at which this excitotoxic cascade is initiated. Using a novel compartmentalised model of site-specific excitotoxin exposure in lower motor neurons in vitro, we found that spinal motor neurons are vulnerable to somatodendritic, but not axonal, excitotoxin exposure. Thus, we developed a model of somatodendritic excitotoxicity in vivo using osmotic mini pumps in Thy-1-YFP mice. We demonstrated that in vivo cell body excitotoxin exposure leads to significant motor neuron death and neuromuscular junction (NMJ) retraction. Using confocal real-time live imaging of the gastrocnemius muscle, we found that NMJ remodelling preceded excitotoxin-induced NMJ degeneration. These findings suggest that excitotoxicity in the spinal cord of individuals with ALS might result in a die-forward mechanism of motor neuron death from the cell body outward, leading to initial distal plasticity, followed by subsequent pathology and degeneration.KEY WORDS: Motor neuron disease, Amyotrophic lateral sclerosis, Excitotoxicity, Lower motor neuron, Excitotoxin exposure     

G37R SOD1 mutant alters mitochondrial complex I activity, Ca(2+) uptake and ATP production

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by selective death of motor neurons. Mutations in Cu/Zn superoxide dismutase-1 (SOD1) cause familial ALS but the molecular mechanisms whereby these mutations induce motor neuron death remain controversial. Here, we show that stable overexpression of mutant human SOD1 (G37R) - but not wild-type SOD1 (wt-SOD1) - in mouse neuroblastoma cells (N2a) results in morphological abnormalities of mitochondria accompanied by several dysfunctions. Activity of the oxidative phosphorylation complex I was significantly reduced in G37R cells and correlated with lower mitochondrial membrane potential and reduced levels of cytosolic ATP. Using targeted chimeric aequorin we further analyzed the consequences of mitochondrial dysfunction on cellular Ca(2+) handling. Mitochondrial Ca(2+) uptake, elicited by IP(3)-induced Ca(2+) release from endoplasmic reticulum (ER) was significantly reduced in G37R cells, while uptake induced by a brief Ca(2+) pulse was not affected in permeabilized cells. The decreased mitochondrial Ca(2+) uptake resulted in increased cytosolic Ca(2+) transients, whereas ER Ca(2+) load and resting cytosolic Ca(2+) levels were not affected. Together, these findings suggest that the mechanism linking mutant G37R SOD1 and ALS involves mitochondrial respiratory chain deficiency resulting in ATP loss and impairment of mitochondrial and cytosolic Ca(2+) homeostasis.     

PTEN regulates AMPA receptor-mediated cell viability in iPS-derived motor neurons

Excitatory transmission in the brain is commonly mediated by the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors. In amyotrophic lateral sclerosis (ALS), AMPA receptors allow cytotoxic levels of calcium into neurons, contributing to motor neuron injury. We have previously shown that oculomotor neurons resistant to the disease process in ALS show reduced AMPA-mediated inward calcium currents compared with vulnerable spinal motor neurons. We have also shown that PTEN (phosphatase and tensin homolog deleted on chromosome 10) knockdown via siRNA promotes motor neuron survival in models of spinal muscular atrophy (SMA) and ALS. It has been reported that inhibition of PTEN attenuates the death of hippocampal neurons post injury by decreasing the effective translocation of the GluR2 subunit into the membrane. In addition, leptin can regulate AMPA receptor trafficking via PTEN inhibition. Thus, we speculate that manipulation of AMPA receptors by PTEN may represent a potential therapeutic strategy for neuroprotective intervention in ALS and other neurodegenerative disorders. To this end, the first step is to establish a fibroblast–iPS–motor neuron in vitro cell model to study AMPA receptor manipulation. Here we report that iPS-derived motor neurons from human fibroblasts express AMPA receptors. PTEN depletion decreases AMPA receptor expression and AMPA-mediated whole-cell currents, resulting in inhibition of AMPA-induced neuronal death in primary cultured and iPS-derived motor neurons. Taken together, our results imply that PTEN depletion may protect motor neurons by inhibition of excitatory transmission that represents a therapeutic strategy of potential benefit for the amelioration of excitotoxicity in ALS and other neurodegenerative disorders.     

Interactions between mitochondrial bioenergetics and cytoplasmic calcium in cultured cerebellar granule cells

The mitochondrion has moved to the center stage in the drama of the life and death of the neuron. The mitochondrial membrane potential controls the ability of the organelle to generate ATP, generate reactive oxygen species and sequester Ca(2+) entering the cell. Each of these processes interact, and their deconvolution is far from trivial. The cultured cerebellar granule cell provides a model in which knowledge gained from studies on isolated mitochondria can be applied to study the role played by the organelles in the maintenance of Ca(2+) homeostasis in the cell under resting, stimulated and pathophysiological conditions. In particular, mitochondria play a complex role in the response of the neuron to excitotoxic stimulation of NMDA and AMPA-kainate selective glutamate receptors. One goal of research in this area is to provide clues as to possible ways in which modulators of mitochondrial function may be used as neuroprotective agents, since mitochondrial Ca(2+) accumulation seems to play a key role in glutamate excitotoxicity.     

Calcium ions in neuronal degeneration

Neuronal Ca(2+) homeostasis and Ca(2+) signaling regulate multiple neuronal functions, including synaptic transmission, plasticity, and cell survival. Therefore disturbances in Ca(2+) homeostasis can affect the well-being of the neuron in different ways and to various degrees. Ca(2+) homeostasis undergoes subtle dysregulation in the physiological ageing. Products of energy metabolism accumulating with age together with oxidative stress gradually impair Ca(2+) homeostasis, making neurons more vulnerable to additional stress which, in turn, can lead to neuronal degeneration. Neurodegenerative diseases related to aging, such as Alzheimer's disease, Parkinson's disease, or Huntington's disease, develop slowly and are characterized by the positive feedback between Ca(2+) dyshomeostasis and the aggregation of disease-related proteins such as amyloid beta, alfa-synuclein, or huntingtin. Ca(2+) dyshomeostasis escalates with time eventually leading to neuronal loss. Ca(2+) dyshomeostasis in these chronic pathologies comprises mitochondrial and endoplasmic reticulum dysfunction, Ca(2+) buffering impairment, glutamate excitotoxicity and alterations in Ca(2+) entry routes into neurons. Similar changes have been described in a group of multifactorial diseases not related to ageing, such as epilepsy, schizophrenia, amyotrophic lateral sclerosis, or glaucoma. Dysregulation of Ca(2+) homeostasis caused by HIV infection or by sudden accidents, such as brain stroke or traumatic brain injury, leads to rapid neuronal death. The differences between the distinct types of Ca(2+) dyshomeostasis underlying neuronal degeneration in various types of pathologies are not clear. Questions that should be addressed concern the sequence of pathogenic events in an affected neuron and the pattern of progressive degeneration in the brain itself. Moreover, elucidation of the selective vulnerability of various types of neurons affected in the diseases described here will require identification of differences in the types of Ca(2+) homeostasis and signaling among these neurons. This information will be required for improved targeting of Ca(2+) homeostasis and signaling components in future therapeutic strategies, since no effective treatment is currently available to prevent neuronal degeneration in any of the pathologies described here.     

Interaction between glutamate signalling and immune attack in damaging oligodendrocytes

Glutamate is the principal excitatory neurotransmitter in the CNS, but it is also a potent neurotoxin that can kill nerve cells. Glutamate damages oligodendrocytes, like neurons, by excitotoxicity which is caused by sustained activation of AMPA, kainate and NMDA receptors. Glutamate excitotoxicity depends entirely on Ca(2+) overload of the cytoplasm and can be initiated by disruption of glutamate homeostasis. Thus, inhibition of glutamate uptake in isolated oligodendrocytes in vitro and in the optic nerve in vivo, is sufficient to trigger cell death which is prevented by glutamate receptor antagonists. In turn, activated, but not resting microglia, can compromise glutamate homeostasis and induce oligodendrocyte excitotoxicity, which is attenuated either by AMPA/kainate antagonists or by the blockade of the system x(c)- antiporter present in microglia. By contrast, non-lethal, brief, activation of glutamate receptors in oligodendrocytes rapidly sensitizes these cells to complement attack. Intriguingly, these effects are exclusively mediated by kainate receptors which induce Ca(2+) overload of the cytosol and the generation of reactive oxygen species. In conjunction, these observations reveal novel mechanisms by which neuroinflammation alters glutamate homeostasis and triggers oligodendrocyte death. Conversely, they also show how glutamate signaling in oligodendrocytes might induce immune attack. In both instances direct activation of glutamate receptors present in oligodendrocytes plays a pivotal role in either initiating or executing death signals, which might be relevant to the pathogenesis of white matter disorders.     

Innate immunity in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative condition in which motor neurons are selectively targeted. Although the underlying cause remains unclear, evidence suggests a role for innate immunity in disease pathogenesis. Neuroinflammation in areas of motor neuron loss is evident in presymptomatic mouse models of ALS and in human patients. Efforts aimed at attenuating the inflammatory response in ALS animal models have delayed symptom onset and extended survival. Seemingly conversely, attempts to sensitize cells of the innate immune system and modulate their phenotype have also shown efficacy. Effectors of innate immunity in the CNS appear to have ambivalent potential to promote either repair or injury. Because ALS is a syndromic disease in which glutamate excitotoxicity, altered cytoskeletal protein metabolism, oxidative injury, mitochondrial dysfunction and neuroinflammation all contribute to motor neuron degeneration, targeting inflammation via modulation of microglial function therefore holds significant potential as one aspect of therapeutic intervention and could provide insight into the exclusive vulnerability of motor neurons.     

Slow and selective death of spinal motor neurons in vivo by intrathecal infusion of kainic acid: implications for AMPA receptor-mediated excitotoxicity in ALS

Excitotoxicity mediated by alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors has been proposed to play a major role in the selective death of motor neurons in sporadic amyotrophic lateral sclerosis (ALS), and motor neurons are more vulnerable to AMPA receptor-mediated excitotoxicity than are other neuronal subclasses. On the basis of the above evidence, we aimed to develop a rat model of ALS by the long-term activation of AMPA receptors through continuous infusion of kainic acid (KA), an AMPA receptor agonist, into the spinal subarachnoid space. These rats displayed a progressive motor-selective behavioral deficit with delayed loss of spinal motor neurons, mimicking the clinicopathological characteristics of ALS. These changes were significantly ameliorated by co-infusion with 6-nitro-7-sulfamobenso(f)quinoxaline-2,3-dione (NBQX), but not with d(-)-2-amino-5-phosphonovaleric acid (APV), and were exacerbated by co-infusion with cyclothiazide, indicative of an AMPA receptor-mediated mechanism. Among the four AMPA receptor subunits, expression of GluR3 mRNA was selectively up-regulated in motor neurons but not in dorsal horn neurons of the KA-infused rats. The up-regulation of GluR3 mRNA in this model may cause a molecular change that induces the selective vulnerability of motor neurons to KA by increasing the proportion of GluR2-lacking (i.e. calcium-permeable) AMPA receptors. This rat model may be useful in investigating ALS etiology.     

Epigallocatechin-3-gallate protects motor neurons and regulates glutamate level

Epigallocatechin-3-gallate (EGCG) is a major component of green tea polyphenols which displays potential properties of anticancer and neuroprotection. Here we show that protection of motor neuron by EGCG is associated with regulating glutamate level in organotypic culture of rat spinal cord. In this model, EGCG blocked glutamate excitotoxicity caused by threohydroxyaspartate, an inhibitor of glutamate transporter. This property of EGCG may be not due to its intrinsic antioxidative activity, because another antioxidant could not regulate glutamate level under the same condition. These results show that EGCG may be a potential therapeutic candidate for neurodegenerative diseases involving glutamate excitotoxicity such as ALS.     

Role of the N-methyl-d-aspartate receptors complex in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease pathologically characterized by the massive loss of motor neurons in the spinal cord, brain stem and cerebral cortex. There is a consensus in the field that ALS is a multifactorial pathology and a number of possible mechanisms have been suggested. Among the proposed hypothesis, glutamate toxicity has been one of the most investigated. Alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor mediated cell death and impairment of the glutamate-transport system have been suggested to play a central role in the glutamate-mediated motor neuron degeneration. In this context, the role played by the N-methyl-d-aspartate (NMDA) receptor has received considerable less attention notwithstanding its high Ca^2 + permeability, expression in motor neurons and its importance in excitotoxicity. This review overviews the critical role of NMDA-mediated toxicity in ALS, with a particular emphasis on the endogenous modulators of the NMDAR.     

Autophagy activation in glutamate-induced motor neuron loss

Recent literature demonstrated that exposure to excitatory amino acid in specific experimental conditions might produce a defect in the autophagy pathway. Such an effect was observed in motor neurons exposed chronically to glutamate agonists. On the other hand, it is well known that glutamate induces motor neuron death and this is supposed to play a key role in the physiopathology of motor neuron loss in amyotrophic lateral sclerosis (ALS). Similarly, a defective recruitment of autophagy was recently documented in ALS. In the present study we found that exposure of motor neurons to kainic acid produces intracellular changes associated with defective autophagy. In this experimental conditions, pharmacological activation of autophagy rescues the loss of motor neurons.     

Focal degeneration of astrocytes in amyotrophic lateral sclerosis

Astrocytes emerge as key players in motor neuron degeneration in Amyotrophic Lateral Sclerosis (ALS). Whether astrocytes cause direct damage by releasing toxic factors or contribute indirectly through the loss of physiological functions is unclear. Here we identify in the hSOD1(G93A) transgenic mouse model of ALS a degenerative process of the astrocytes, restricted to those directly surrounding spinal motor neurons. This phenomenon manifests with an early onset and becomes significant concomitant with the loss of motor cells and the appearance of clinical symptoms. Contrary to wild-type astrocytes, mutant hSOD1-expressing astrocytes are highly vulnerable to glutamate and undergo cell death mediated by the metabotropic type-5 receptor (mGluR5). Blocking mGluR5 in vivo slows down astrocytic degeneration, delays the onset of the disease and slightly extends survival in hSOD1(G93A) transgenic mice. We propose that excitotoxicity in ALS affects both motor neurons and astrocytes, favouring their local interactive degeneration. This new mechanistic hypothesis has implications for therapeutic interventions.     

Genetics of amyotrophic lateral sclerosis: an update

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder involving both upper motor neurons (UMN) and lower motor neurons (LMN). Enormous research has been done in the past few decades in unveiling the genetics of ALS, successfully identifying at least fifteen candidate genes associated with familial and sporadic ALS. Numerous studies attempting to define the pathogenesis of ALS have identified several plausible determinants and molecular pathways leading to motor neuron degeneration, which include oxidative stress, glutamate excitotoxicity, apoptosis, abnormal neurofilament function, protein misfolding and subsequent aggregation, impairment of RNA processing, defects in axonal transport, changes in endosomal trafficking, increased inflammation, and mitochondrial dysfunction. This review is to update the recent discoveries in genetics of ALS, which may provide insight information to help us better understanding of the disease neuropathogenesis.     

Caspase-3 cleaves and inactivates the glutamate transporter EAAT2

EAAT2 is a high affinity, Na+-dependent glutamate transporter with predominant astroglial localization. It accounts for the clearance of the bulk of glutamate released at central nervous system synapses and therefore has a crucial role in shaping glutamatergic neurotransmission and limiting excitotoxicity. Caspase-3 activation and impairment in expression and activity of EAAT2 are two distinct molecular mechanisms occurring in human amyotrophic lateral sclerosis (ALS) and in the transgenic rodent model of the disease. Excitotoxicity caused by down-regulation of EAAT2 is thought to be a contributing factor to motor neuron death in ALS. In this study, we report the novel evidence that caspase-3 cleaves EAAT2 at a unique site located in the cytosolic C-terminal domain of the transporter, a finding that links excitotoxicity and activation of caspase-3 as converging mechanisms in the pathogenesis of ALS. Caspase-3 cleavage of EAAT2 leads to a drastic and selective inhibition of this transporter. Heterologous expression of mutant SOD1 proteins linked to the familial form of ALS leads to inhibition of EAAT2 through a mechanism that largely involves activation of caspase-3 and cleavage of the transporter. In addition, we found evidence in spinal cord homogenates of mutant SOD1 ALS mice of a truncated form of EAAT2, likely deriving from caspase-3-mediated proteolytic cleavage, which appeared concurrently to the loss of EAAT2 immunoreactivity and to increased expression of activated caspase-3. Taken together, our findings suggest that caspase-3 cleavage of EAAT2 is one mechanism responsible for the impairment of glutamate uptake in mutant SOD1-linked ALS.     

肌萎缩性侧索硬化症动物模型的应用进展

肌萎缩性侧索硬化症（ALS）是运动神经元选择性死亡而导致运动功能障碍的神经性疾病,是成年人运动神经元病中最常见的疾病。已有很多学说讨论其发病机制,并且建立了ALS动物模型。随着现代生物学的发展和不同学科间的相互渗入,各种治疗策略在ALS模型实验中得到实践并有望用于临床。简要综述了ALS治疗方法在转基因动物模型中的研究进展。