Mutations of human Cu,Zn superoxide dismutase (SOD) are found in about 20 percent of patients with familial amyotrophic lateral sclerosis (ALS). Expression of high levels of human SOD containing a substitution of glycine to alanine at position 93--a change that has little effect on enzyme activity--caused motor neuron disease in transgenic mice. The mice became paralyzed in one or more limbs as a result of motor neuron loss from the spinal cord and died by 5 to 6 months of age. The results show that dominant, gain-of-function mutations in SOD contribute to the pathogenesis of familial ALS.

One of the common neurological complications in patients with the acquired immune deficiency syndrome (AIDS) is a subacute encephalopathy with progressive dementia. By using the techniques of cocultivation for virus isolation, in situ hybridization, immunocytochemistry, and transmission electron microscopy, the identity of an important cell type that supports replication of the AIDS retrovirus in brain tissue was determined in two affected individuals. These cells were mononucleated and multinucleated macrophages that actively synthesized viral RNA and produced progeny virions in the brains of the patients. Infected brain macrophages may serve as a reservoir for virus and as a vehicle for viral dissemination in the infected host.

Twenty percent of the familial form of amyotrophic lateral sclerosis (ALS) is caused by mutations in the Cu, Zn-superoxide dismutase gene (SOD1) through the gain of a toxic function. The nature of this toxic function of mutant SOD1 has remained largely unknown. Here we show that WT SOD1 not only hastens onset of the ALS phenotype but can also convert an unaffected phenotype to an ALS phenotype in mutant SOD1 transgenic mouse models. Further analyses of the single-and double-transgenic mice revealed that conversion of mutant SOD1 from a soluble form to an aggregated and detergent-insoluble form was associated with development of the ALS phenotype in transgenic mice. Conversion of WT SOD1 from a soluble form to an aggregated and insoluble form also correlates with exacerbation of the disease or conversion to a disease phenotype in double-transgenic mice. This conversion, observed in the mitochondrial fraction of the spinal cord, involved formation of insoluble SOD1 dimers and multimers that are crosslinked through intermolecular disulfide bonds via oxidation of cysteine residues in SOD1. Our data thus show a molecular mechanism by which SOD1, an important protein in cellular defense against free radicals, is converted to aggregated and apparently ALS-associated toxic dimers and multimers by redox processes. These findings provide evidence of direct links among oxidation, protein aggregation, mitochondrial damage, and SOD1-mediated ALS, with possible applications to the aging process and other late-onset neurodegenerative disorders. Importantly, rational therapy based on these observations can now be developed and tested.crosslinked ͉ disulfide bonds ͉ oxidation ͉ protein aggregation ͉ neurodegeneration A myotrophic lateral sclerosis (ALS) is a progressive paralytic disorder caused by degeneration of the motor neurons in brain and spinal cord (1). Most of the ALS cases are sporadic, with Ϸ5-10% being familial. The progressive paralysis in ALS usually affects respiratory function, leading to ventilatory failure and death; 50% of patients die within 3 years of onset of symptoms, and 90% die within 5 years. The juvenile form of ALS usually has a prolonged course of two to four decades. There is no known effective treatment for this fatal disease, although marginal delay in mortality has been noted with the drug riluzole (2).Familial ALS can be transmitted as either a dominant or a recessive trait. We and our collaborators have previously shown that mutations in the Cu, Zn-superoxide dismutase gene (SOD1) are associated with Ϸ20% of familial ALS cases (3, 4). The pathogenic mechanisms underlying this disease are still largely unknown. Most, but not all, transgenic mice overexpressing ALS-associated SOD1 mutants develop ALS-like disease (5), and transgenic mice overexpressing human WT SOD1 (hwtSOD1) or SOD1-deficient mice do not develop ALS-like disease (5, 6), suggesting that mutant SOD1 requires a threshold of expression to cause the disease through the gain of a toxic property.Thus far, Ͼ100 mutations, widely distrib...

SummaryThe role of epitope spreading in the pathology of relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) was examined. Using peripherally induced immunologic tolerance as a probe to analyze the neuropathologic T cell repertoire, we show that the majority of the immunopathologic reactivity during the acute phase of R-EAE in SJL/J mice induced by active immunization with the intact proteolipid (PLP) molecule is directed at the PLP139-151 epitope and that responses to secondary encephalitogenic PLP epitopes may contribute to the later relapsing phases of disease. Intermolecular epitope spreading was demonstrated by showing the development of T cell responses to PLP139-151 after acute disease in mice in which R-EAE was initiated by the transfer ofT cells specific for the non-cross-reactive MBP84-104 determinant. Intramolecular epitope spreading was demonstrated by showing that endogenous host T cells specific for a secondary encephalitogenic PLP epitope (PLP178-191) are demonstrable by both splenic T cell proliferative and in vivo delayed-type hypersensitivity responses in mice in which acute central nervous system damage was initiated by T cells reactive with the immunodominant, non-cross-reactive PLP139-151 sequence. The PLP178-191-specific responses are activated as a result of and correlate with the degree of acute tissue damage, since they do not develop in mice tolerized to the initiating epitope before expression of acute disease. Most importantly, we show that the PLP178-191-specific responses are capable of mediating R-EAE upon adoptive secondary transfer to naive recipient mice. Furthermore, induction of tolerance to intact PLP (which inhibits responses to both the initiating PLP139-151 epitope and to the PLP178-191 epitope) after the acute disease episode is sufficient to prevent relapsing disease. These results strongly support a contributory role ofT cell responses to epitopes released as a result of acute tissue damage to the immunopathogenesis of relapsing clinical episodes and have important implications for the design of antigenspecific immunotherapies for the treatment of chronic autoimmune disorders in humans.t~ lapsing experimental autoimmune encephalomyelitis (R-EAE) 1 is a CD4 + Thl-mediated demyelinating disease of the central nervous system (CNS) (1) that is inducible in genetically susceptible animals by immunization with myelin basic protein (MBP) or proteolipid protein (PLP) (2, 3) or synthetic peptides corresponding to the major encephalitogenic epitopes of MBP and PLP (4, 5). Alternatively, R-EAE The first two authors contributed equally to this work and should both be considered first authors.1 Abbreviations used in this paper: CNS, central nervous system; DTH, delayed-type hypersensitivity; ECDI, 1-ethyl-3-(3-dimethylaminopropyl)-carhodiimide HC1; MBP, myelin basic protein; MMS, mean maximal disease severity; MS, multiple sclerosis; PLP, proteolipid protein; K-EAE, relapsing experimental autoimmune encephalomyelitis; SP, splenocyte. may be transferred to naive rec...

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