Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0002736 (amyotrophic lateral sclerosis)
 19,048 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In many of autosomal dominant diseases such as familial amyotrophic lateral sclerosis (ALS) with Cu/Zn superoxide dismutase (SOD1) mutation, a missense point mutation may induce the disease by its gain of adverse property. Similar 'gain of toxic function' of mutant protein is predicted to cause cell death in other autosomal dominant neurodegenerative diseases such as familial Alzheimer disease, prion disease, polyglutamine diseases and Parkinson disease. In all these familial diseases, one rational approach to therapy is to develop a method to specifically eliminate the aberrant protein. Duplex of 21-nt RNA, known as siRNA, has recently emerged as a powerful tool to silence gene. Mutant-allele specific gene silencing with siRNA was showed in familial ALS and Machado-Joseph diseases. We made the transgenic (Tg) mouse of modified small interfering RNA (siRNA). By crossing this anti-SOD1 siRNA Tg mouse with a SOD1(G93A) Tg mouse as a model for ALS, siRNA halted the development of disease by inhibiting mutant G93A SOD1. Our results support the feasibility of utilizing siRNA-based gene therapy of neurodegenerative diseases of autosomal dominant inheritance.
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PMID:[RNAi and neurological disease]. 1644 77

Induction of COX-2 expression and enzymatic activity promotes neuronal injury in a number of models of neurological disease. Inhibition of COX-2 activity, either genetically or pharmacologically, has been shown to be neuroprotective in rodent models of stroke, Parkinson's disease, and amyotrophic lateral sclerosis. Inhibition of COX activity with nonsteroidal anti-inflammatory drugs (NSAIDs) reduces inflammation and amyloid accumulation in murine transgenic models of Familial Alzheimer's disease, and the use of NSAIDs decreases the risk of developing Alzheimer's disease in healthy aging populations. COX-mediated neuronal injury is presumed be due to downstream effects of one or more prostaglandin products including PGE2, PGD2, PGF2alpha, PGI2 (prostacylin) and TXA2 (thromboxane) that effect cellular changes through activation of specific prostaglandin receptor subtypes and second messenger systems. In this proceeding, we review recent data demonstrating effects of prostaglandin signaling on neuronal viability that are paradoxically protective, when taken in the context that COX-2 induces neuronal injury in the setting of excitotoxicity. Conversely, in the context of an inflammatory stimulus, the EP2 receptor enhances neuronal injury. These findings argue for an additional level of complexity in the prostaglandin response in neurological disease.
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PMID:Function of COX-2 and prostaglandins in neurological disease. 1790 52

Cyclooxygenase-2 (COX-2) is a neuronal immediate early gene that is regulated by N-methyl d aspartate (NMDA) receptor activity. COX-2 enzymatic activity catalyzes the first committed step in prostaglandin synthesis. Recent studies demonstrate an emerging role for the downstream PGE(2) EP2 receptor in diverse models of activity-dependent synaptic plasticity and a significant function in models of neurological disease including cerebral ischemia, Familial Alzheimer's disease, and Familial amyotrophic lateral sclerosis. Little is known, however, about the normal function of the EP2 receptor in behavior and cognition. Here we report that deletion of the EP2 receptor leads to significant cognitive deficits in standard tests of fear and social memory. EP2-/- mice also demonstrated impaired prepulse inhibition (PPI) and heightened anxiety, but normal startle reactivity, exploratory behavior, and spatial reference memory. This complex behavioral phenotype of EP2-/- mice was associated with a deficit in long-term depression (LTD) in hippocampus. Our findings suggest that PGE(2) signaling via the EP2 receptors plays an important role in cognitive and emotional behaviors that recapitulate some aspects of human psychopathology related to schizophrenia.
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PMID:Impaired cognition, sensorimotor gating, and hippocampal long-term depression in mice lacking the prostaglandin E2 EP2 receptor. 1941 71