Intrathecal immune response in patients with the post-polio syndrome.

BACKGROUND. The syndrome of progressive muscular atrophy decades after acute paralytic poliomyelitis (post-polio syndrome) is not well understood. The theory that physiologic changes and aging cause the new weakness does not explain the immunologic abnormalities reported in some patients. An alternative explanation is persistent or recurrent poliovirus infection. METHODS. We assessed the intrathecal antibody response to poliovirus and intrathecal production of interleukin-2 and soluble interleukin-2 receptors in 36 patients with the post-polio syndrome and 67 controls (including 13 who had had poliomyelitis but had no new symptoms and 18 with amyotrophic lateral sclerosis). Intrathecal antibody responses to measles, mumps, herpes simplex, and varicella zoster viruses were also determined. RESULTS. Oligoclonal IgM bands specific to poliovirus were detected in the cerebrospinal fluid of 21 of the 36 patients with the post-polio syndrome (58 percent) but in none of the control group (P less than 0.0001). In quantitative studies there was evidence of increased intrathecal synthesis of IgM antibodies to poliovirus only among the patients with the post-polio syndrome; there was no increased synthesis of IgM to measles, mumps, herpes simplex, or varicella zoster viruses. The patients with post-polio syndrome had significantly higher mean (+/- SD) (cerebrospinal fluid levels of interleukin-2 and soluble interleukin-2 receptors than the controls (8.1 +/- 5.3 vs. 1.4 +/- 0.8 U per milliliter and 159.6 +/- 102.9 vs. 10.7 +/- 6.2 U per milliliter, respectively). The intrathecal synthesis of IgM antibodies to poliovirus correlated with the cerebrospinal fluid concentrations of interleukin-2 (P less than 0.0005) and soluble interleukin-2 receptors (P less than 0.001). CONCLUSIONS. An intrathecal immune response against poliovirus is present in many patients with the post-polio syndrome. In some of these patients the recrudescence of muscle weakness may be caused by persistent or recurrent infection of neural cells with the poliovirus.     

Inhibition of terminal axonal sprouting by serum from patients with amyotrophic lateral sclerosis

To investigate the pathogenesis of amyotrophic lateral sclerosis, we compared the effect of serum from patients with this disease on the regenerative sprouting of terminal axons in botulinum-treated mouse gluteus muscle with the effects of serum from controls and from patients with diabetic peripheral neuropathy. Serum from 9 of 19 patients with the sporadic form of amyotrophic lateral sclerosis and from 2 of 6 patients with the familial form caused a reduction in the proportion of sprouting terminal axons, as compared with that found in muscles treated with serum from controls or diabetic patients. Immunoglobulin from patients with amyotrophic lateral sclerosis, when tested on immunoblots, recognized a 56-kilodalton protein secreted by denervated rat diaphragm muscle; rabbit antiserum raised against this protein also suppressed terminal axonal sprouting. Thus, we have detected an antibody in the serum of patients with amyotrophic lateral sclerosis that inhibits sprouting of neurons and subsequent reinnervation of skeletal muscle. Whether this antibody is of primary pathogenic importance or represents a secondary response to neuromuscular destruction is not known. In either case, serum from patients with amyotrophic lateral sclerosis may provide reagents for studies of the trophic communications between muscle and motor neurons.     

Etiogenic factors present in the cerebrospinal fluid from amyotrophic lateral sclerosis patients induce predominantly pro-inflammatory responses in microglia

Background

Microglial cell-associated neuroinflammation is considered as a potential contributor to the pathophysiology of sporadic amyotrophic lateral sclerosis. However, the specific role of microglia in the disease pathogenesis remains to be elucidated.

Methods

We studied the activation profiles of the microglial cultures exposed to the cerebrospinal fluid from these patients which recapitulates the neurodegeneration seen in sporadic amyotrophic lateral sclerosis. This was done by investigating the morphological and functional changes including the expression levels of prostaglandin E2 (PGE2), cyclooxygenase-2 (COX-2), TNF-α, IL-6, IFN-γ, IL-10, inducible nitric oxide synthase (iNOS), arginase, and trophic factors. We also studied the effect of chitotriosidase, the inflammatory protein found upregulated in the cerebrospinal fluid from amyotrophic lateral sclerosis patients, on these cultures.

Results

We report that the cerebrospinal fluid from amyotrophic lateral sclerosis patients could induce an early and potent response in the form of microglial activation, skewed primarily towards a pro-inflammatory profile. It was seen in the form of upregulation of the pro-inflammatory cytokines and factors including IL-6, TNF-α, iNOS, COX-2, and PGE2. Concomitantly, a downregulation of beneficial trophic factors and anti-inflammatory markers including VEGF, glial cell line-derived neurotrophic factor, and IFN-γ was seen. In addition, chitotriosidase-1 appeared to act specifically via the microglial cells.

Conclusion

Our findings demonstrate that the cerebrospinal fluid from amyotrophic lateral sclerosis patients holds enough cues to induce microglial inflammatory processes as an early event, which may contribute to the neurodegeneration seen in the sporadic amyotrophic lateral sclerosis. These findings highlight the dynamic role of microglial cells in the pathogenesis of the disease, thus suggesting the need for a multidimensional and temporally guarded therapeutic approach targeting the inflammatory pathways for its treatment.

     

Slowly progressing lower motor neuron disease caused by a novel duplication mutation in exon 1 of the SOD1 gene

Familial amyotrophic lateral sclerosis accounts for about 5% of all cases of the neurodegenerative disorder amyotrophic lateral sclerosis. Genetic mutations in Cu/Zn superoxide dismutase (SOD1) have been associated with one kind of familial amyotrophic lateral sclerosis (ALS1). We identified a novel duplication mutation in exon 1 of the SOD1 gene in a Japanese family whose members had lower motor neuron diseases. The patients showed slow disease progression, with the onset of lower limb muscle weakness and exertional dyspnea. Some patients had mild motor and sensory neuropathy and/or bladder dysfunction, which is further evidence that SOD1 mutation results in a predominantly lower motor neuron phenotype.     

The pseudopolyneuritic form of amyotrophic lateral sclerosis (Patrikios' disease)

The line distinguishing motor neuron diseases (MNDs) from motor neuropathies is sometimes blurred. Among MNDs, the pseudopolyneuritic form of amyotrophic lateral sclerosis (ALS) strictly mimics a neuropathy. We describe the clinical and electrophysiological features in the early stages of the pseudopolyneuritic ALS, and assess the disease progression in eight patients. Early symptoms were unilateral foot-drop and, less commonly, paraparesis. At the clinical examination, weakness of distal and proximal leg muscles was often detected, while the hand muscles were rarely involved and craniobulbar muscles were spared. Definite upper motor neuron signs were rare in the early stages of the disease. Electromyography (EMG) showed active denervation in the lower limbs of all patients (distal > proximal) and in the paraspinal muscles of 7 patients (lumbosacral > thoracic), and more rarely in the upper limbs. Transcranial magnetic stimulation (TMS) yielded abnormal responses (low amplitude or absent cortical motor evoked potentials and prolonged central motor conduction time) in most lower-limb recordings, while mild abnormalities were rarely observed in the upper limbs. Haematologic and cerebrospinal fluid examinations were normal. Brain and spinal MRI showed no significant abnormalities. After a three years follow-up on seven patients, all cases were nonambulatory and had upper limb weakness, and most of them had bulbar dysfunction. The electrophysiological finding of both upper and lower motor neuron involvement of the lower limbs in the early stages of the disease could be a useful marker to distinguish the pseudopolyneuritic form of ALS from other MNDs and motor neuropathies.     

Serum antibodies to L-type calcium channels in patients with amyotrophic lateral sclerosis.

BACKGROUND AND METHODS. Sporadic amyotrophic lateral sclerosis is a chronic, progressive degenerative disease of the motor neurons of the spinal cord and motor cortex. The cause is unknown. Recent electrophysiologic studies in animals indicate that immunoglobulins from patients with this disease alter presynaptic voltage-dependent calcium currents and calcium-dependent release of neurotransmitters. To determine whether similar interactions might be identified biochemically, we used an enzyme-linked immunosorbent assay (ELISA) to detect the reaction of serum IgG with purified complexes of L-type voltage-gated calcium channels from rabbit skeletal muscle. The results from patients with amyotrophic lateral sclerosis were compared with those obtained from patients with other types of motor neuron disease, patients with autoimmune and non-autoimmune neurologic diseases, and normal subjects. RESULTS. Serum samples from 36 of 48 patients with sporadic amyotrophic lateral sclerosis (75 percent) contained IgG that reacted with L-type calcium-channel protein, and serum reactivity on ELISA correlated with the rate of disease progression (Spearman rank-correlation coefficient, 0.62). Reactive serum was present in only 1 of 25 normal subjects and 1 of 35 control patients with no motor neuron disease. Antibodies to L-type voltage-gated calcium channels were identified in 6 of 9 patients with Lambert-Eaton syndrome, and in 3 of 15 patients with Guillain-Barré syndrome. CONCLUSIONS. Antibodies to L-type voltage-gated calcium channels are present in the serum of patients with amyotrophic lateral sclerosis, and antibody titers correlate with the rate of disease progression. Together with previous data, these results suggest a role for autoimmune mechanisms in the pathogenesis of sporadic amyotrophic lateral sclerosis.     

On the development of markers for pathological TDP-43 in amyotrophic lateral sclerosis with and without dementia

Pathological 43-kDa transactive response sequence DNA-binding protein (TDP-43) has been recognized as the major disease protein in amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with ubiquitin positive, tau and α-synuclein negative inclusions (FTLD-U) and the transitional forms between these multisystem conditions. In order to develop TDP-43 into a successful ALS biomarker, the natural history of TDP-43 pathology needs to be characterized and the underlying pathophysiology established. Here we propose a spatial and temporal "two-axes" model of central nervous system vulnerability for TDP-43 linked degeneration and review recent studies on potential biomarkers related to pathological TDP-43 in the cerebrospinal fluid (CSF), blood, and skeletal muscle. The model includes the following two arms: Firstly, a "motor neuron disease" or "spinal cord/brainstem to motor cortex" axis (with degeneration possibly ascending from the lower motor neurons to the upper motor neurons); and secondly, a "dementia" or "corticoid/allocortex to neocortex" axis (with a probable spread of TDP-43 linked degeneration from the mediotemporal lobe to wider mesocortical and neocortical brain areas). At the cellular level, there is a gradual disappearance of normal TDP-43 in the nucleus in combination with the formation of pathological aggregates in the cell body and cellular processes, which can also be used to identify the stage of the disease process. Moreover, TDP-43 lesions in subpial/subependymal or perivascular localizations have been noted, and this might account for increased CSF and blood TDP-43 levels through mechanisms that remain to be elucidated.     

神经电生理检测对肌萎缩侧索硬化症患者的早期诊断价值

目的：探讨肌萎缩侧索硬化症(ALS)与脊髓型颈椎病(CSM)的神经电生理改变的差异。方法：对60例ALS与CSM患者进行常规肌电图(EMG)、神经电图(ENoG)检测。EMG检测包括三肢体肌、胸锁乳突肌、胸段棘旁肌等肌肉，观察静息状态时自发电位，测定运动单位电位(MUP)的时限、波幅，大力收缩时的募集相。测定运动、感觉神经的传导速度(MCV，SCV)及动作电位的末端潜伏期(ML)、波幅(Amp)。结果：ALS与CSM中自发电位的异常率分别为：胸锁乳突肌39％和17．5％，胸段棘旁肌分别为93．3％和3．3％，肢体肌分别为88．1％和75％，ALS患者MUP时限、波幅的增高不同于CSM患者，差异均有显著意义。结论：胸段棘旁肌EMG阳性率高、简便易行，为早期鉴别诊断ALS与CSM提供了更敏感的依据。同时表明电生理检测可作为ALS可疑或ALS与CSM两病并存患者的随访观察及判定病情和预后的客观指标。     

Dysphagia in patients with the post-polio syndrome

BACKGROUND AND METHODS. Dysphagia may develop in some patients many years after an attack of acute paralytic poliomyelitis. To identify clinical or subclinical signs of oropharyngeal dysfunction, we examined 32 patients (mean age, 48.9 years) with the post-polio syndrome (defined by new weakness in the limbs). Of the 32 patients, 14 had symptoms of new swallowing difficulties, and 18 were asymptomatic in this respect; 12 had a history of bulbar involvement during acute poliomyelitis. Swallowing function was assessed objectively by ultrasonography, videofluoroscopy, and an oral motor index score for 10 components of oral function. RESULTS. All but 1 of the 32 patients, regardless of whether they had new symptoms or previous bulbar involvement, had some abnormality on detailed testing of oropharyngeal function; only 2 patients had any signs of aspiration. The mean oral motor index score (a quantitative measure of oral sensorimotor function) in the patients was higher than that in age-matched normal subjects (P less than 0.001). Videofluoroscopy showed abnormalities of varying severity, including unilateral bolus transport through the pharynx, pooling in the valleculae or pyriform sinuses, delayed pharyngeal constriction, and impaired tongue movements. On ultrasonography, the mean (+/- SD) duration of wet swallows was significantly longer in the symptomatic patients than in the asymptomatic patients (2.67 +/- 0.70 vs. 1.65 +/- 0.42 seconds). The four patients who were reexamined two years later had objective signs of worsening oropharyngeal function and corresponding new symptoms. CONCLUSIONS. In patients with the post-polio syndrome, the bulbar muscles often have clinical or subclinical signs of dysfunction. These abnormalities suggest that in bulbar neurons there is a slowly progressive deterioration similar to that in the muscles of the limbs.     

Two consecutive fasciculation potentials having different motor unit origins are an electromyographically pathognomonic finding of ALS

To electrophysiologically diagnose amyotrophic lateral sclerosis (ALS), fasciculation potentials (FPs) were evaluated in each wasted muscle in 12 ALS and 14 other neurogenic disorders (non-ALS patients). Various types of FPs were observed in ALS. The number of discharged FPs and firing rate of FPs were significantly increased in ALS compared to those in non-ALS. These findings indicate that more motor units take part in discharging FPs in ALS than in non-ALS, and that injured lower motor neurons exhibit hyperexcitability. Although nine of 12 ALS patients showed two consecutive FPs having different motor unit origins, non-ALS patients did not show such FPs. Since the two consecutive FPs having different motor unit origins reflect an involvement of both upper and lower motor neurons, these potentials are an electrophysiologically pathognomonic finding to ALS.     

Vgf is a novel biomarker associated with muscle weakness in amyotrophic lateral sclerosis (ALS), with a potential role in disease pathogenesis

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. Previous proteomic evidence revealed that the content of certain peptide fragments including Vgf-derived peptide aa 398-411 (Vgf_398-411) of the precursor Vgf protein in the cerebral spinal fluid (CSF) correctly identified patients with ALS from normal and disease controls. Using quantitative ELISA immunoassay we found that the CSF levels of Vgf decreases with muscle weakness in patients with ALS. In SOD1 G93A transgenic mice, loss of full-length Vgf content in CSF, serum and in SMI-32 immunopositive spinal cord motor neurons is noted in asymptomatic animals (approximately 75 days old) and continues to show a progressive decline as animals weaken. In vitro studies show that viral-mediated exogenous Vgf expression in primary mixed spinal cord neuron cultures attenuates excitotoxic injury. Thus, while Vgf may be a reliable biomarker of progression of muscle weakness in patients with ALS, restoration of Vgf expression in spinal cord motor neurons may therapeutically rescue spinal cord motorneurons against excitotoxic injury.     

Motor neuron firing dysfunction in spastic patients with primary lateral sclerosis

Patients with corticospinal tract dysfunction have slow voluntary movements with brisk stretch reflexes and spasticity. Previous studies reported reduced firing rates of motor units during voluntary contraction. To assess whether this firing behavior occurs because motor neurons do not respond normally to excitatory inputs, we studied motor units in patients with primary lateral sclerosis, a degenerative syndrome of progressive spasticity. Firing rates were measured from motor units in the wrist extensor muscles at varying levels of voluntary contraction < or =10% maximal force. At each force level, the firing rate was measured with and without added muscle vibration, a maneuver that repetitively activates muscle spindles. In motor units from age-matched control subjects, the firing rate increased with successively stronger contractions as well as with the addition of vibration at each force level. In patients with primary lateral sclerosis, motor-unit firing rates remained stable, or in some cases declined, with progressively stronger contractions or with muscle vibration. We conclude that excitatory inputs produce a blunted response in motor neurons in patients with primary lateral sclerosis compared with age-matched controls. The potential explanations include abnormal activation of voltage-activated channels that produce stable membrane plateaus at low voltages, abnormal recruitment of the motor pool, or tonic inhibition of motor neurons.     

Mechanisms for neuronal degeneration in amyotrophic lateral sclerosis and in models of motor neuron death (Review)

Amyotrophic lateral sclerosis (ALS), also referred to as motor neurone disease, is a fatal neurological disease that is characterized clinically by progressive muscle weakness, muscle atrophy, and eventual paralysis. The neuropathology of ALS is primary degeneration of upper (motor cortical) and lower (brainstem and spinal) motor neurons. The amyotrophy refers to the neurogenic atrophy of affected muscle groups, and the lateral sclerosis refers to the hardening of the lateral white matter funiculus in spinal cord (corresponding to degeneration of the corticospinal tract) found at autopsy. Because the mechanisms for the motor neuron degeneration in ALS are not understood, this disease has no precisely known causes and no effective treatments. Very recent studies have identified that the degeneration of motor neurons in ALS is a form of apoptotic cell death that may occur by an abnormal programmed cell death (PCD) mechanism. In order to treat ALS effectively, we need to understand the mechanisms for motor neuron apoptosis more completely. Future studies need to further identify the signals for PCD activation in neurons as they relate to the pathogenesis of ALS and to clarify the molecular pathways leading to motor neuron apoptosis in animal and cell culture model systems. These studies should lead to a better understanding of motor neuron death and to the design of new therapeutic experiments critical for the future treatment of ALS.     

Pathogenic effects of amyotrophic lateral sclerosis-linked mutation in D-amino acid oxidase are mediated by D-serine

Amyotrophic lateral sclerosis is a neuromuscular disease characterized by selective loss of motor neurons leading to fatal paralysis. We previously reported a coding mutation in D–amino acid oxidase (R199W DAO) associated with familial amyotrophic lateral sclerosis. DAO metabolizes D-serine, a co-agonist at the N-methyl-D-aspartic acid receptor. We investigated the mechanisms mediating the pathogenic effects of R199W DAO on motor neuron survival and showed that expression of glial R199W DAO is sufficient to induce apoptosis in cocultured motor neurons and this is sensitive to 5,7-dichloro-4-hydroxyquinoline-2-carboxylic acid, an N-methyl-d-aspartic acid receptor antagonist selective for the D-serine/glycine site. R199W DAO activates protein aggregation and autophagy, which is also sensitive to this antagonist. Using immunocytochemistry, we showed that D-serine and DAO were abundant in spinal cord motor neurons and depleted in amyotrophic lateral sclerosis. In summary, the toxic effects of R199W DAO on motor neurons can be mediated directly by expression in motor neurons or by astrocytes in coculture, R199W DAO promotes autophagy and its pathogenic effects are at least in part mediated via the N-methyl-d-aspartic acid receptor.     

Postencephalitic Parkinson's disease,amyotrophic lateral sclerosis on Guam and influenza revisited: focusing on neurofibrillary tangles and the trail of tau

Circumstantial evidence links neuropathological changes in postencephalitic Parkinson's disease and amyotrophic lateral sclerosis on Guam to the 1918 influenza pandemic. Postencephalitic Parkinson's disease and amyotrophic lateral sclerosis have neuronal neurofibrillary tangles that anatomically correlate with clinical signs and symptoms. Occurrences of the disorders peaked in the early 1950s and are now disappearing. Neurovirulent influenza associated with the lethal 1918 pandemic is suggested as the etiology of both diseases. Permissive tissue antigens are considered an important contributing factor. Neurofibrillary tangles also correlate with signs and symptoms in Alzheimer's disease. Oxidative stress may be the pathological process that induces neurofibrillary tangles. Tangles contain abnormally phosphorylated tau. In Alzheimer's disease, tau is present in cerebrospinal fluid and is deposited in corpora amylacea, demonstrating the direction of cerebrospinal fluid flow.     

Identification of a novel Cys146X mutation of SOD1 in familial amyotrophic lateral sclerosis by whole-exome sequencing

PurposeFamilial amyotrophic lateral sclerosis has been linked to mutations in 15 genes, and it is believed these genes account for less than 20–30% of Chinese patients with familial amyotrophic lateral sclerosis. Of the 163 different superoxide dismutase 1 gene mutations in amyotrophic lateral sclerosis 1, only 6.1% of them were from individuals of Chinese origin. Therefore, to quickly learn the causative gene for patients with familial amyotrophic lateral sclerosis in a Chinese pedigree, we opted to apply whole-exome sequencing as a diagnostic tool.MethodsTo avoid time-consuming screening of known familial amyotrophic lateral sclerosis candidate genes by PCR-Sanger sequencing, we conducted whole-exome sequencing toward selected individuals of a four-generation familial amyotrophic lateral sclerosis family.ResultsPatients in the family showed autosomal dominant features, as well as a mean onset age of 35.3 years, and a mean duration of 2.1 years. By deep sequencing analysis, we identified a novel p.Cys146X SOD1 mutation in all examined patients. Genotype–phenotype and SOD1 structural model analysis revealed the effects of the Cys57–Cys146 disulfide bond formation and the C-terminal dimer contact region on the disease phenotypes.ConclusionThe Cys146X mutation causes familial amyotrophic lateral sclerosis with severe phenotypes. Whole-exome sequencing becomes an attractive diagnostic tool for identifying causative genes, particularly for neurological disorders with unusual phenotypes, pleiotropic malformations, multiple known candidate genes, and complicated inheritance patterns.Genet Med 2012:14(9):823–826     

FUS is not dysregulated by the spinal bulbar muscular atrophy androgen receptor polyglutamine repeat expansion

Spinal bulbar muscular atrophy (SBMA) and amyotrophic lateral sclerosis are two distinct forms of motor neuron disease with different genetic causes, pathology, and clinical course. However, both disorders are characterized by the progressive loss of lower motor neurons and by a similar protective response to growth factors in animal models, therefore raising the possibility of an overlap in the final pathogenic cascade. Mutations in the FUS gene and fused in sarcoma (FUS) protein pathology have now been identified in some amyotrophic lateral sclerosis cases, while a CAG expansion in the androgen receptor gene is known to cause SBMA. Recently, multiple lines of evidence have identified FUS as a major target of the androgen receptor, suggesting that FUS could be dysregulated in SBMA motor neurons. We have investigated this possibility by using a well-established mouse model of SBMA and our analysis of primary motor neuron cultures, spinal cords, and microdissected motor neurons show no evidence for FUS dysregulation.     

52例肌萎缩侧索硬化症的临床及肌电图分析

目的：探讨肌萎缩侧索硬化（ALS）的临床表现及肌电图（EMG）特点,企为早期诊断提供依据。方法：回顾性研究近3年来收治的52例ALS患者的一般资料、临床表现、EMG及其它实验室检查,分析其发病特点、临床特征及EMG特点。结果：50例为散发病例,2例有ALS家族史。男性36例,女性16例,平均发病年龄54．67岁,平均病程13．69个月。起病形式均为缓慢起病,逐渐加重。几乎均以肢体肌无力、肌萎缩为首发症状,大部分患者肢体远端症状重于近端。主要临床表现为肢体肌和舌肌无力、萎缩及肌束震颤、锥体束征、构音障碍、呛咳及吞咽困难。无感觉障碍。EMG表现为广泛神经原性异常。颈椎磁共振（MRI）示74％的患者合并颈椎病。结论：ALS的诊断主要依靠临床表现及EMG检查。EMG、MRI及一些血液学检查是诊断及鉴别诊断该病的重要辅助检查手段。     

Amyloid precursor protein (APP) contributes to pathology in the SOD1G93A mouse model of amyotrophic lateral sclerosis

In amyotrophic lateral sclerosis (ALS), the progressive loss of motor neurons is accompanied by extensive muscle denervation, resulting in paralysis and ultimately death. Upregulation of amyloid beta (A4) precursor protein (APP) in muscle fibres coincides with symptom onset in both sporadic ALS patients and the SOD1(G93A) mouse model of familial ALS. We have further characterized this response in SOD1(G93A) mice and also revealed elevated levels of β-amyloid (Aβ) peptides in the SOD1(G93A) spinal cord, which were predominantly localized within motor neurons and their surrounding glial cells. We therefore examined the effect of genetic ablation of APP on disease progression in SOD1(G93A) mice, which significantly improved multiple disease parameters, including innervation, motor function, muscle contractile characteristics, motor unit and motor neuron survival. These results therefore strongly suggest that APP actively contributes to SOD1(G93A)-mediated pathology. Together with observations from ALS cases, this study indicates that APP may contribute to human ALS pathology.