[“Agonist Function

Introducing mutant genes into mice can reproduce some features of these diseases. Autosomal recessive diseases, which usually lack the functional protein encoded by the mutant gene, can often be modeled by gene knockout strategies.In both groups of disorders, gene knockout or overexpression of the genes that influence pathogenic pathways have prov ided insight into disease mechanisms and potential therapeutic targets.These model systems can also be used to evaluate novel treatments and expedite the path to clinical trials.Here we focus on the familial forms of AD and spinal muscular atrophy. In the case of FAD and FALS, we anticipate that understanding the inher ited illnesseswill shed light on the more common sporadic forms of AD and ALS.In the case of SMA, all cases are attributable to the same genetic mechanism.Mental functions and activ ities of daily living become progressively impaired.The clinical signs of AD result from selective degeneration of neurons in brain regions critical for memory, cognitive performance and personality. Dysfunction and death of these neurons lead to reduced numbers of synaptic markers in their target fields; the disruption of synaptic communication is manifested by mental impairments and, finally, severe dementia.Two types of intracellular and extracellular protein aggregates found in the brain are a pathological hallmark of AD. Neurofibrillary tangles are inclusions located within cell bodies and proximal dendrites, and within filamentous swellings in distal axons and synaptic terminals.Hyperphosphorylated isoforms of the microtubuleassociated protein tau, which assemble into poorly soluble paired helical filaments, are central feature of these neurofibrillary tangles.The extracellular aggregates in the brain of individuals with AD result from elevated levels of A, a kD amyloid peptide derived by cleavage of the amyloid precursor protein. A monomers form oligomers and multimers, which assemble into cysteine protofilaments and then fibrils. Eventually, A fibrils are deposited as the amyloid cores of neuritic or senile plaques, which are complex structures also containing dystrophic neurites, astrocytes and microglia.Both neurofibrillary lesions and plaques are preferentially localized to the cortex, hippocampus and amygdala.Schematic diagram of a neuron showing an extracellular amyloid plaque in the target field with a central core of A fibrils surrounded by dystrophic neurites, astrocytes and microglia.Such mutations are identified in at least three different genes: APP, PS and PS. APP is a type I transmembrane protein expressed in many different cell types, but particularly abundant in neurons. Pathogenic A peptides are generated via cleavage of APP by BACE. The levels and distributions of APP and these proamyloidogenic cleavage enzymes in neurons, and in particular BACE, are hypothesized to be the principal determinants of high levels of A in the brain.A variety of APP mutations reported in cases of FAD are near cleavage sites involved in formation of A. This longer A peptide is thought to promote the formation of A aggregates and amyloid plaques.In contrast, APP mutationswithin the A peptide domain do not elevate the level of A but may cause amyloidosis by increasing A oligomer or protofibril formation.PS influences APP processing, but it is not clear whether PS itself acts as the protease, functions as a Diethylstilbestrol cofactor critical for the activity of secretase, or exerts its influence via trafficking of APP to the proper compartment for secretase cleavage.

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