Development of Immunization Approaches to Amyotrophic Lateral Sclerosis
Development of Immunization Approaches to Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons in the brain and spinal cord. Mutations in the gene encoding superoxide dismutase (SOD1) remain the major known genetic causes associated with ALS. Evidence suggests that the toxicity of SOD1 mutations is related to the abnormal misfolding and aggregation of mutant SOD1 proteins. The discovery of a secretion pathway for mutant SOD1 increased the possibility of using immunization approaches to reduce or neutralize the burden of toxic SOD1 species in the nervous system. Both active and passive immunization protocols were successful in delaying the onset of disease and mortality in transgenic mice expressing mutant SOD1. Owing to the potential adverse immune responses, immunization strategies need to be considered cautiously before being tested in human clinical trials. Critical issues for development of human immunotherapy will be discussed including the routes and methods of antibody delivery, the specificity of antibodies and immune responses, the penetration through the BBB and the time to start treatment. Prophylactic immunotherapy may become a conceivable approach for SOD1-linked ALS patients providing that the treatment is not overly invasive and can be implemented at reasonable cost. This article reviews how innate and adaptive immunity can affect the pathogenesis of ALS and how harnessing the immune system through immunization approaches might offer promising future therapeutic avenues.
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the death of large motor neurons in the cerebral cortex and spinal cord. Dysfunction and death of these cell populations lead to progressive muscle weakness, atrophy and, ultimately, paralysis and death usually within 3 to 5 years after disease onset. The estimated worldwide incidence for the disease is approximately two per 100,000 of total population and the life-long risk of developing ALS is approximately one in 2000. The disease occurs in sporadic (90%) and familial forms (10%). Despite many years of intensive study, very few genes have been unequivocally implicated in ALS. The well-known superoxide dismutase 1 (SOD1) gene accounts for approximately 2–5% of all ALS cases. Recently, mutations in two other genes, TARDBP and FUS have been found in ALS patients. Rare mutations in other genes, such as ANG, ALS2, DCTN1, MAPT, NEFH, PRPH, SETX, VAPB, VEGF (for a review see [3]) and more recently, ELP3 and FIG4, are also associated with motor neuron diseases. To date, mutations in the SOD1 gene have remained the major known genetic causes associated with ALS. However, the mechanism whereby mutant SOD1 causes specific degeneration of motor neurons remains unclear. A toxic gain of function rather than a loss of SOD1 enzymatic activity is believed to be involved. The favored hypothesis at this time is that toxicity of SOD1 mutants is related to the misfolding and aggregation of SOD1 species (Figure 1). In this model, the acquired propensity of SOD1 to misfold owing to genetic mutations, improper metallation of the protein, loss of disulfide bound, post-translational modification or yet unknown environmental factors, would favor the conversion of reduced monomers into oligomeric and aggregated forms with toxic properties. Owing to exposure of hydrophobic residues to the environment, the monomeric reduced form of SOD1 would exhibit abnormal subcellular localization to compartments such as mitochondria and endoplasmic reticulum (ER)–Golgi. However, it is not clear which conformational SOD1 species and oligomers cause ALS. Deleterious effects could result from the interaction of misfolded SOD1 species with essential cellular components, such as Bcl-2, from their recruitment to the outer membrane of mitochondria or from overwhelming the capacity of the protein-folding chaperones and/or of ubiquitin proteasome pathway to degrade important cellular regulatory factors. The misfolded proteins can also form aggregates that might sequester important cellular components causing cytotoxicity. Recent studies have demonstrated that a fraction of SOD1 can be translocated via the ER–Golgi network and that chromogranins, which are proteins abundant in motor neurons, interneurons and activated astrocytes, may act as chaperone-like proteins to promote secretion of misfolded SOD1 mutants. Moreover, extracellular mutant SOD1 can induce microgliosis and motor neuron death. Such a ALS pathogenic mechanism based on toxicity of secreted SOD1 mutants is in line with findings that the disease is not strictly autonomous to motor neurons and that toxicity can propagate from one cell to another.
(Enlarge Image)
Figure 1.
Toxicity model based on misfolding and aggregation of mutant superoxide dismutase.
Following its synthesis, there is dimerization of the SOD1 protein, which involves formation of intramolecular disulfide bond as well as metallation by zinc and copper. The misfolding of SOD1 by diverse factors would favor the conversion of reduced monomers into aggregated forms with toxic properties.
ER: Endoplasmic reticulum; SOD: Superoxide dismutase.
Although ALS is a disease that is not considered to be triggered by the immune system, recent studies with transgenic mouse models demonstrated that immune responses may play an important role in the degenerative process. The immune system may have beneficial or adverse effects in the disease depending on the context. For example, the beneficial or detrimental effect of the microglial response to activation of innate immunity or to cytokine administration is influenced by a number of factors including the presence or absence of ALS-linked mutant SOD1 expression in these cells. Recently, some experimental approaches aiming to induce a humoral immune response in mouse models of ALS have resulted in beneficial effects. In this article, we will review how components of the innate and adaptive immunity can affect the pathogenesis of ALS. We will also discuss how harnessing the immune system through vaccination approaches might offer promising future therapeutic avenues.
Abstract and Introduction
Abstract
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by loss of motor neurons in the brain and spinal cord. Mutations in the gene encoding superoxide dismutase (SOD1) remain the major known genetic causes associated with ALS. Evidence suggests that the toxicity of SOD1 mutations is related to the abnormal misfolding and aggregation of mutant SOD1 proteins. The discovery of a secretion pathway for mutant SOD1 increased the possibility of using immunization approaches to reduce or neutralize the burden of toxic SOD1 species in the nervous system. Both active and passive immunization protocols were successful in delaying the onset of disease and mortality in transgenic mice expressing mutant SOD1. Owing to the potential adverse immune responses, immunization strategies need to be considered cautiously before being tested in human clinical trials. Critical issues for development of human immunotherapy will be discussed including the routes and methods of antibody delivery, the specificity of antibodies and immune responses, the penetration through the BBB and the time to start treatment. Prophylactic immunotherapy may become a conceivable approach for SOD1-linked ALS patients providing that the treatment is not overly invasive and can be implemented at reasonable cost. This article reviews how innate and adaptive immunity can affect the pathogenesis of ALS and how harnessing the immune system through immunization approaches might offer promising future therapeutic avenues.
Introduction
Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disease characterized by the death of large motor neurons in the cerebral cortex and spinal cord. Dysfunction and death of these cell populations lead to progressive muscle weakness, atrophy and, ultimately, paralysis and death usually within 3 to 5 years after disease onset. The estimated worldwide incidence for the disease is approximately two per 100,000 of total population and the life-long risk of developing ALS is approximately one in 2000. The disease occurs in sporadic (90%) and familial forms (10%). Despite many years of intensive study, very few genes have been unequivocally implicated in ALS. The well-known superoxide dismutase 1 (SOD1) gene accounts for approximately 2–5% of all ALS cases. Recently, mutations in two other genes, TARDBP and FUS have been found in ALS patients. Rare mutations in other genes, such as ANG, ALS2, DCTN1, MAPT, NEFH, PRPH, SETX, VAPB, VEGF (for a review see [3]) and more recently, ELP3 and FIG4, are also associated with motor neuron diseases. To date, mutations in the SOD1 gene have remained the major known genetic causes associated with ALS. However, the mechanism whereby mutant SOD1 causes specific degeneration of motor neurons remains unclear. A toxic gain of function rather than a loss of SOD1 enzymatic activity is believed to be involved. The favored hypothesis at this time is that toxicity of SOD1 mutants is related to the misfolding and aggregation of SOD1 species (Figure 1). In this model, the acquired propensity of SOD1 to misfold owing to genetic mutations, improper metallation of the protein, loss of disulfide bound, post-translational modification or yet unknown environmental factors, would favor the conversion of reduced monomers into oligomeric and aggregated forms with toxic properties. Owing to exposure of hydrophobic residues to the environment, the monomeric reduced form of SOD1 would exhibit abnormal subcellular localization to compartments such as mitochondria and endoplasmic reticulum (ER)–Golgi. However, it is not clear which conformational SOD1 species and oligomers cause ALS. Deleterious effects could result from the interaction of misfolded SOD1 species with essential cellular components, such as Bcl-2, from their recruitment to the outer membrane of mitochondria or from overwhelming the capacity of the protein-folding chaperones and/or of ubiquitin proteasome pathway to degrade important cellular regulatory factors. The misfolded proteins can also form aggregates that might sequester important cellular components causing cytotoxicity. Recent studies have demonstrated that a fraction of SOD1 can be translocated via the ER–Golgi network and that chromogranins, which are proteins abundant in motor neurons, interneurons and activated astrocytes, may act as chaperone-like proteins to promote secretion of misfolded SOD1 mutants. Moreover, extracellular mutant SOD1 can induce microgliosis and motor neuron death. Such a ALS pathogenic mechanism based on toxicity of secreted SOD1 mutants is in line with findings that the disease is not strictly autonomous to motor neurons and that toxicity can propagate from one cell to another.
(Enlarge Image)
Figure 1.
Toxicity model based on misfolding and aggregation of mutant superoxide dismutase.
Following its synthesis, there is dimerization of the SOD1 protein, which involves formation of intramolecular disulfide bond as well as metallation by zinc and copper. The misfolding of SOD1 by diverse factors would favor the conversion of reduced monomers into aggregated forms with toxic properties.
ER: Endoplasmic reticulum; SOD: Superoxide dismutase.
Although ALS is a disease that is not considered to be triggered by the immune system, recent studies with transgenic mouse models demonstrated that immune responses may play an important role in the degenerative process. The immune system may have beneficial or adverse effects in the disease depending on the context. For example, the beneficial or detrimental effect of the microglial response to activation of innate immunity or to cytokine administration is influenced by a number of factors including the presence or absence of ALS-linked mutant SOD1 expression in these cells. Recently, some experimental approaches aiming to induce a humoral immune response in mouse models of ALS have resulted in beneficial effects. In this article, we will review how components of the innate and adaptive immunity can affect the pathogenesis of ALS. We will also discuss how harnessing the immune system through vaccination approaches might offer promising future therapeutic avenues.