To date, different misconversion of O sense mutations have been identified in the SOD gene.These mutat ions are scattered throughout the prote in and are not preferentially localized near the active site or the dimer interface.Although some FALS SOD mutants show reduced enzymatic activ ities, many retain full activ ity.The mutant enzyme causes selective neuronal degeneration through a gain of toxic property, cons is tentwith au tosomaldom inantinheritance. The presence of ubiquitin aggregates containing mutant SOD protein in affected neurons raises the possibility that the defect is due to essential molecules being sequestered away by the aggregates.Alternatively, the misfolded mutant SOD could catalyze aberrant reactions.A gene Riboflavin termed ALS, on chromosome, is linked to juvenile ALS in several families.Mutations in ALS are inherited as autosomal recessive and lead to a premature truncation, suggesting that the disease is associated with a loss of ALS function.Thus, genetic approaches to ablate the gene encoding ALS may Fluoxetine provide useful mouse models of this rare form of ALS.The GR SOD transgenic mice provide an excellent illustration of these models.GR SOD, which retains full SOD activity, accumulates to times the endogenous levels in the spinal cord, and the levels of the mutant protein influence the age of onset.Toxic SOD is transpor ted anterograde in axons, and early on, it accumulates in axons, where it is associated with structural pathology.Approximately months before the appearance of clinical signs, SOD accumulates in irregular, swollen, intraparenchymal portions of motor axons, and the axonal cytoskeleton and axonal transport are abnormal.Eventually, the number of motor neurons is reduced.These mouse models recapitulate the major clinical and pathological hallmarks of ALS.Several potential therapeutics have been tested with unencouraging results, including vitamin E and selenium, riluzole and gabapentin, and the copper chelator dpenicillamine.At present, treatment with creatine seems to have the most robust pharmacological influence on the disease; oral administration of creatine to GA SOD mice resulted in a dosedependent improvement in motor tasks and extended survival.The molecular mechanisms whereby mutant SOD causes selective motor neuron death have not yet been defined.One proposalisth atthetoxicpropertyof mutantSOD invo lves mutationinduced conformational changes in SOD that result in aberrant oxidative activities.In this scenario, cell dysfunction and death could be initiated by aberrant oxidative chemistries catalyzed by the copper atom bound in the active site of mutant SOD. Thus, CCS is necessaryfor eff ic ient copper incorporat ion into SOD in motor neurons.However, although the absence of the CCS results in a significant reduction in the level of copperloaded mutant SOD, it has no effect on the onset, progression or pathology of motor neuron disease in mutant SOD mice.A pathological hallmark of ALS is the accumulation of neurofilaments in proximal axons and cell bodies of motor neurons.The progeny of SOD mutant mice crossed to mice expressing an NFH galactosidase fusion protein, which crosslinks neurofilaments and prevents their export to axons, has no effect on disease progression.In contrast, the lifespan of SOD mutant mice was moderately increased in the absence of neurofilaments when NFL was ablated.However, crosses with mice overexpressing wildtype NFL or NFH resulted in sparing of motor neurons, attenuation of disease progression and increased life span.

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