Kegg Pathway: Amyotrophic lateral sclerosis (ALS)

J Biol Chem. 2008 Jul 17;
Rudrabhatla P, Zheng YL, Amin ND, Kesavapany S, Albers W, Pant HC

Aberrant phosphorylation of neuronal cytoskeletal proteins is a key pathological event in neurodegenerative disorders such as Alzheimer's disease (AD) and Amyotrophic lateral sclerosis (ALS), but the underlying mechanisms are still unclear. Previous studies have shown that Pin1, a peptidylprolyl cis/trans-isomerase may be actively involved in the regulation of tau hyperphosphorylation in AD. Here, we show that Pin1 modulates oxidative stress-induced NF-H phosphorylation. In an in vitro kinase assay, the addition of Pin1 substantially increased phosphorylation of NF-H KSP repeats by proline directed kinases, Erk1/2, Cdk5/p35 and JNK3 in a concentration-dependent manner. In vivo, dominant-negative (DN) Pin1 and Pin1 siRNA inhibited EGF-induced NF-H phosphorylation. Since oxidative stress plays an important role in the pathogenesis of neurodegenerative diseases, we studied the role of Pin1 in stressed cortical neurons and HEK293 cells. Both hydrogen peroxide (H2O2) and heat stresses induce phosphorylation of NF-H in transfected HEK293 cells and primary cortical cultures. Knockdown of Pin1 by transfected Pin1 siRNA and DNPin1 rescues the effect of stress-induced NF-H phosphorylation. The H2O2 and heat shock induced perikaryal phospho-NF-H accumulations and neuronal apoptosis was rescued by inhibition of Pin1 in cortical neurons. The c-Jun amino terminal kinase 3 (JNK3), a brain specific JNK isoform, is activated under oxidative and heat stresses and inhibition of Pin1 by Pin1 siRNA and dominant negative (DN) Pin1 inhibits this pathway. These results implicate Pin1 as a possible modulator of stress-induced NF-H phosphorylation as seen in neurodegenerative disorders like AD and ALS. Thus, Pin1 may be a potential therapeutic target for these diseases.

Brain Res. 2008 Jul 2;
Rohn TT

The TAR DNA-binding protein-43 (TDP-43) has been identified as a major constituent of inclusions found in frontotemporal dementia with ubiquitin-positive inclusions (FTLD-U) and Amyotrophic lateral sclerosis (ALS). To determine a possible role for TDP-43 in Alzheimer's disease (AD), a site-directed caspase-cleavage antibody to TDP-43 based upon a known caspase-3 cleavage consensus site within TDP- 43 at position D219 was designed. In vitro, this antibody labeled the predicted 25 kDa caspase-cleavage fragment of TDP-43 without labeling full-length TDP-43 following digestion of recombinant TDP-43 with caspase-3 or treatment of HeLa cells with staurosporine. Application of this antibody in postmortem brain sections indicated the presence of caspase-cleaved TDP-43 in Hirano bodies, tangles, reactive astrocytes and neuritic plaques of the AD brain. Caspase-cleaved TDP-43 also co-localized with ubiquitin labeled neurons as well as dystrophic neurites within plaque regions. These results suggest that caspase-cleaved TDP-43 is a major pathological finding in AD and may contribute to the neurodegeneration associated with this disease.

Environ Health Perspect. 2008 Jul; 116(7): 943-7
Kamel F, Umbach DM, Stallone L, Richards M, Hu H, Sandler DP

BACKGROUND: Reasons for the variability in survival among ALS cases are unknown but may include exposure to environmental neurotoxicants. OBJECTIVES: We aimed to determine whether lead exposure, assessed by measuring blood and bone lead levels, is associated with survival in Amyotrophic lateral sclerosis (ALS). METHODS: We evaluated the relationship of lead exposure to ALS survival in 110 cases from a case-control study conducted in New England in 1993-1996 that included measurements of blood and bone lead. We retrieved information on date and cause of death through 31 December 2003 from the National Death Index Plus and the Social Security Administration Death Index. We evaluated the relationship of survival to lead exposure using Cox proportional hazard analysis, with adjustment for age, sex, and smoking. RESULTS: We found mortality data for 100 of 110 cases; 93 of 100 death certificates mentioned ALS. Median survival from diagnosis to death was 28 months. Shorter survival was associated with older age at diagnosis, female sex, bulbar onset, shorter interval between symptom onset and diagnosis, and reduced lung function. Shorter survival from diagnosis to death had a weak inverse association with blood lead (hazard ratio = 0.9; 95% confidence interval, 0.8-1.0) and a stronger inverse association with patella lead (0.5; 0.2-1.0) and tibia lead (0.3; 0.1-0.7); similar results were found for survival from symptom onset to death. CONCLUSIONS: These results suggest that lead exposure is associated with longer survival in ALS cases and, if confirmed, may shed light on mechanisms involved in disease progression.

Phys Med Rehabil Clin N Am. 2008 Aug; 19(3): 633-51
Distad BJ, Meekins GD, Liou LL, Weiss MD, Carter GT, Miller RG

Amyotrophic lateral sclerosis (ALS) is a devastating condition characterized by progressive muscle wasting, inanition, respiratory failure, and death within approximately 2 to 5 years of onset. ALS is among the most common neuromuscular conditions, with an overall prevalence in the world of ~ 5 to 7 cases/100,000 population. Epidemiologic studies have identified some potential risk factors for developing ALS, including a high-fat, low-fiber diet; cigarette smoking; slimness and athleticism; and living in urban areas. Between 5% and 10% of ALS is genetic, with up to 11 genetic loci identified. Although understanding of the pathophysiology of this disease has advanced over the past 60 years, scant progress has been made regarding effective treatment. The authors review the current understanding of the pathogenic mechanisms of ALS and approaches to treating the disease.

Phys Med Rehabil Clin N Am. 2008 Aug; 19(3): 619-31
Mayadev AS, Weiss MD, Jane Distad B, Krivickas LS, Carter GT

Amyotrophic lateral sclerosis (ALS) is a devastating, progressive motor neuron disorder that poses a myriad of clinical problems. Patients who have ALS are best cared for in a multidisciplinary fashion, with involvement of clinicians from various specialties, including neurology, physical medicine and rehabilitation, pulmonary medicine, clinical nurse specialists or nurse practitioners, physical and occupational therapists, speech language pathologists, dietitians, psychologists, social workers, and case managers. This article provides a summary of the current research into the rehabilitation of ALS, including the role of exercise, spasticity management, mood disorders, pain, and palliative care.

Phys Med Rehabil Clin N Am. 2008 Aug; 19(3): 607-17
Woolley SC, Jonathan S Katz

Cognitive impairment in Amyotrophic lateral sclerosis (ALS) is correlated with pathologic and radiographic changes in cerebral cortex beyond the motor regions. Clinically, evidence of impairment can be detected in up to 50 percent of patients through direct neuropsychological testing, although frank frontotemporal dementia (FTD) occurs in a limited percentage. Behavioral changes are also common and can be characterized primarily by the presence of increased apathy. Determining the underlying causes of cognitive or behavioral change may be confounded by several disease-related factors, including fatigue, respiratory compromise, depression, and treatment with medications such as riluzole. Studies assessing the evolution and relative risk for cognitive and behavioral impairment in ALS suggest at least two types of patients: those who have clear FTD in whom cognitive decline develops gradually and those who have mild cognitive or behavioral impairments in whom progression either does not occur or is difficult to detect. Limited data suggest that cognition and behavior influence compliance, management, and survival, although this requires further assessment.

Phys Med Rehabil Clin N Am. 2008 Aug; 19(3): 591-605
Bromberg MB

Although quality of life is difficult to define clearly, a number of instruments and questionnaires have been developed and applied to patients who have Amyotrophic lateral sclerosis (ALS). This article reviews the spectrum of quality-of-life questionnaires and instruments used for ALS and the data generated from them. It discusses positive and negative factors that can affect quality of life for the patient and caregiver and concludes with suggestions for ongoing management to enhance quality of life.

Phys Med Rehabil Clin N Am. 2008 Aug; 19(3): 573-89
Rosenfeld J, Ellis A

Compromised nutrition leading to weight loss is a common and significant problem in the Amyotrophic lateral sclerosis (ALS) patient population. The benefit of aggressive and early nutritional therapy can profoundly influence the disease course, quality of life, and survival. This article reviews the role of nutrition, both as sustenance and treatment for patients who have ALS. Self-medication with dietary supplements has become increasingly popular within this patient population. Despite their popularity, the efficacy of these compounds has been largely unsupported by formal clinical trials. Available data will be highlighted to provide a basis upon which to advise patients requesting guidance.

Phys Med Rehabil Clin N Am. 2008 Aug; 19(3): 545-57
Chen A, Montes J, Mitsumoto H

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting the motor nervous system. It causes progressive and cumulative physical disabilities in patients, and leads to eventual death due to respiratory muscle failure. The disease is diverse in its presentation, course, and progression. We do not yet fully understand the cause or causes of the disease, nor the mechanisms for its progression; thus, we lack effective means for treating this disease. Currently, we rely on a multidisciplinary approach to symptomatically manage and care for patients who have ALS. In this article, the authors review the literature on the role of exercise in patients who have ALS, and briefly compare what is known about exercise in other neuromuscular diseases.

Phys Med Rehabil Clin N Am. 2008 Aug; 19(3): 533-43
Lou JS

Fatigue is a common and potentially debilitating symptom of Amyotrophic lateral sclerosis (ALS). Questionnaire studies show that ALS subjects have increased subjective fatigue. Physiologic studies demonstrate that ALS subjects have increased physical fatigue, both central and peripheral in origin. No treatment has been proved effective through evidence-based medicine; however, modafinil (Provigil) may be a helpful pharmacologic treatment. Palliative care measures, such as noninvasive ventilation and high-frequency chest wall oscillation, may also reduce fatigue.

Phys Med Rehabil Clin N Am. 2008 Aug; 19(3): 461-477
Ravits J, Traynor BJ

New knowledge of the structure and function of the human genome and novel genomic technologies are being applied to the study of sporadic Amyotrophic lateral sclerosis (ALS). These studies can examine tens to hundreds of thousands of items at once, and depend on sophisticated computer processing. Current studies are focused on genetic susceptibility and gene expression and future studies will likely focus on structural variation, gene regulation and non-protein coding regions. The hope is that they will lead to deeper understanding of molecular aspects of the disease and to rational therapeutic targets.

Phys Med Rehabil Clin N Am. 2008 Aug; 19(3): 441-59
Raibon E, Todd LM, Möller T

Amyotrophic lateral sclerosis (ALS) was initially known as Charcot's sclerosis, named after the French neurobiologist and physician Jean-Martin Charcot who first described this type of muscular atrophy in the early nineteenth century. In the United States, ALS became widely known as Lou Gehrig's disease after the famous baseball player who succumbed to the disease in the late 1930s. Currently, ALS is the most common motor neuron disease, with a worldwide incidence of 8 cases per 100,000 population per year. Familial forms constitute approximately 5% to 10% of all cases. Onset increases with age, with a peak in the seventh decade and a slight preponderance (relative risk, 1.3-1.5) among men compared with women. Rapid progression of motor neuron loss leads to death an average of 3 to 5 years after symptom onset. The cause of ALS remains unknown and there is still no curative therapy.

Phys Med Rehabil Clin N Am. 2008 Aug; 19(3): 429-439
Siddique N, Siddique T

Amyotrophic lateral sclerosis (ALS) was first described by Charcot in 1869 as what we would now call a sporadic disease-a disease believed to occur without a strong genetic influence. Only within the past 10 years has it been possible to fully explore genetic influence on disorders that seem to occur sporadically but likely result from the convergence of multiple genetic and environmental factors. This article reviews the genetics of familial ALS and summarizes current investigations of genetic influence in sporadic ALS. Genetic study clearly offers the potential for identification of molecular targets that would allow development of rational therapies for various forms of ALS, but much work remains.

Exp Neurol. 2008 Jun 24;
Boston-Howes W, Williams EO, Bogush A, Scolere M, Pasinelli P, Trotti D

Synaptic accumulation of glutamate causes neuronal death in many neurodegenerative pathologies such as Amyotrophic lateral sclerosis. Drugs capable of increasing glutamate uptake could therefore be therapeutically effective. We screened in a cell-based assay a library of 1040 FDA-approved drugs and nutrients for compounds that could enhance glutamate uptake. Nordihydroguaiaretic acid (NDGA), an anti-inflammatory drug that inhibits lipoxygensases, potently enhanced glutamate uptake in MN-1 cells. Given subcutaneously at 1 mg/day for 30 days in mice, NDGA increased glutamate uptake in spinal cord synaptosomes persistently throughout the treatment. However, when administered following the same regimen to the SOD1-G93A transgenic mouse model of ALS at disease onset, NDGA did not extend survival of these mice. We found that NDGA failed to sustain increased glutamate uptake in the SOD1-G93A mice despite an initial upregulation measured during the first 10 days of treatment. SOD1-G93A mice displayed a progressive increase in spinal cord expression levels of the efflux transporter P-glycoprotein beginning at disease onset. This increase was not a specific consequence of the NDGA treatment as we have measured it in untreated SOD1-G93A mice. Because P-glycoproteins control the extrusion of a broad range of toxins and xenobiotics and are responsible for drug resistance in many diseases including cancer and brain diseases such as epilepsy, we propose that the failure of NDGA in maintaining glutamate uptake upregulated in SOD1-G93A mice and its therapeutic inefficacy are due to acquired pharmacoresistance mediated by the increased expression of P-glycoprotein.

J Neurochem. 2008 Jun 30;
Krishnan J, Vannuvel K, Andries M, Waelkens E, Robberecht W, Van Den Bosch L

Amyotrophic lateral sclerosis (ALS) is a chronic, adult-onset neurodegenerative disorder characterized by the selective loss of upper and lower motor neurons, resulting in severe atrophy of muscles and death. Although the exact pathogenic mechanism of mutant superoxide dismutase 1 (SOD1) causing familial ALS is still elusive, toxic protein aggregation leading to insufficiency of chaperones is one of the main hypotheses. In this study, we investigated the effect of overexpressing one of these chaperones, heat shock protein 27 (Hsp27), in ALS. Mice overexpressing the human, mutant SOD1(G93A) were crossed with mice that ubiquitously overexpressed human Hsp27. Even though the single transgenic hHsp27 mice showed protection against spinal cord ischemia, the double transgenic SOD1(G93A)/hHsp27 mice did not live longer, and did not show a significant delay in the onset of disease compared to their SOD1(G93A) littermates. There was no protective effect of hHsp27 overexpression on the motor neurons and on the mutant SOD1 aggregates in the double transgenic SOD1(G93A)/hHsp27 mice. In conclusion, despite the protective action against acute motor neuron injury, Hsp27 alone is not sufficient to protect against the chronic motor neuron injury due to the presence of mutant SOD1.

Amyotroph lateral Scler. 2008 Jul 11; 1-6
Roccatagliata L, Bonzano L, Mancardi G, Canepa C, Caponnetto C

We prospectively investigated pathological modifications in the corticospinal tract (CST), by diffusion tensor imaging (DTI) in 14 patients with sporadic Amyotrophic lateral sclerosis (ALS) and 12 healthy volunteers. We used a validated automated method to accurately measure the in vivo thickness of the cerebral cortex. We found a reduction of precentral cortical ribbon thickness in ALS patients with respect to control subjects. DTI metrics demonstrated disorganization of the CST, as characterized by decreased fractional anisotropy (FA) and increased Apparent Diffusion Coefficient in ALS patients with respect to control subjects. Decreased mean FA values along the CST significantly correlated with clinical measures of pyramidal and bulbar impairment. Quantitative analysis of MR data shows that thinning of the motor cortex coexists with CST damage in ALS patients.

Amyotroph lateral Scler. 2008 Jul 11; 1-7
Murphy V, Felgoise SH, Walsh SM, Simmons Z

Amyotrophic lateral sclerosis (ALS) often is associated with a particularly intensive caregiving experience, and the well-being of caregivers impacts that of patients. Thus, identification of factors leading to distress in caregivers may provide avenues for intervention that will help both the caregiver and the patient. We prospectively examined caregivers' social problem solving skills, the quality of the patient-caregiver relationship, caregivers' spirituality and religiousness, and the ways in which these impact caregivers' quality of life (QoL) and psychological morbidity in 75 caregivers of ALS patients. Data were analyzed through correlational and hierarchical multiple regression analyses. Social problem solving and spirituality were the best predictors of caregivers' QoL, accounting for 15.6% and 7.8% of the variance in QoL, respectively (F (2, 69) = 11.83, p<.001). Social problem solving also predicted and accounted for 25.4% of the variance in psychological morbidity (F (1, 71) = 25.571, p<.001). Level of care provided did not predict either QoL or psychological morbidity in caregivers. In conclusion, the problem-solving skills of ALS caregivers are an important determinant of caregiver well-being. Developing interventions to teach ALS caregivers effective methods of problem solving would probably be beneficial to this population.

Amyotroph lateral Scler. 2008 Jul 10; 1-10
Del Signore SJ, Amante DJ, Kim J, Stack EC, Goodrich S, Cormier K, Smith K, Cudkowicz ME, Ferrante RJ

Recent evidence suggests that transcriptional dysregulation may play a role in the pathogenesis of Amyotrophic lateral sclerosis (ALS). The histone deacetylase inhibitor, sodium phenylbutyrate (NaPB), is neuroprotective and corrects aberrant gene transcription in ALS mice and has recently been shown to be safe and tolerable in ALS patients while improving hypoacetylation. Since many patients are already on riluzole, it is important to ensure that any proposed therapy does not result in negative synergy with riluzole. The combined treatment of riluzole and NaPB significantly extended survival and improved both the clinical and neuropathological phenotypes in G93A transgenic ALS mice beyond either agent alone. Combination therapy increased survival by 21.5%, compared to the separate administration of riluzole (7.5%) and NaPB (12.8%), while improving both body weight loss and grip strength. The data show that the combined treatment was synergistic. In addition, riluzole/NaPB treatment ameliorated gross lumbar and ventral horn atrophy, attenuated lumbar ventral horn neuronal cell death, and decreased reactive astrogliosis. Riluzole/NaPB administration increased acetylation at H4 and increased NF-kappaB p50 translocation to the nucleus in G93A mice, consistent with a therapeutic effect. These data suggest that NaPB may not interfere with the pharmacologic action of riluzole in ALS patients.

Amyotroph lateral Scler. 2008 Jul 10; 1-9
Landers JE, Shi L, Cho TJ, Glass JD, Shaw CE, Nigel Leigh P, Diekstra F, Polak M, Rodriguez-Leyva I, Niemann S, Traynor BJ, McKenna-Yasek D, Sapp PC, Al-Chalabi A, Wills AM, Brown RH

Amyotrophic lateral sclerosis (ALS) is a progressive, neurodegenerative disorder of upper and lower motor neurons. Genetic variants in the paraoxonase gene cluster have been associated with susceptibility to sporadic ALS. Because these studies have yielded conflicting results, we have further investigated this association in a larger data set. Twenty SNPs spanning the paraoxonase gene cluster were genotyped on a panel of 597 case and 692 control samples and tested for association with risk of sporadic ALS and with ALS sub-phenotypes. Our study revealed two SNPs, rs987539 and rs2074351, within the paraoxonase gene cluster that are associated with susceptibility to sporadic ALS (uncorrected p=6.47E-04 and 7.87E-04, respectively). None of the 20 SNPs displayed significant associations with age of onset, site of onset or disease survival. Using a sliding window approach, we have also identified a 5-SNP haplotype that is significantly associated with risk of sporadic ALS (p=2.75E-05). We conclude that a common haplotype within the PON1 promoter region is associated with susceptibility to sporadic ALS.

Cell Death Differ. 2008 Jul 11;
Rossi D, Brambilla L, Valori CF, Roncoroni C, Crugnola A, Yokota T, Bredesen DE, Volterra A

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.Cell Death and Differentiation advance online publication, 11 July 2008; doi:10.1038/cdd.2008.99.