|Ubiquitin over-expression phenotypes and ubiquitin gene molecular misreading during aging in Drosophila melanogaster.|
Hoe, N; Huang, CM; Landis, G; Verhage, M; Ford, D; Yang, J; van Leeuwen, FW; Tower, J
Molecular Misreading (MM) is the inaccurate conversion of genomic information into aberrant proteins. For example, when RNA polymerase II transcribes a GAGAG motif it synthesizes at low frequency RNA with a two-base deletion. If the deletion occurs in a coding region, translation will result in production of misframed proteins. During mammalian aging, misframed versions of human amyloid precursor protein (hApp) and ubiquitin (hUbb) accumulate in the aggregates characteristic of neurodegenerative diseases, suggesting dysfunctional degradation or clearance. Here cDNA clones encoding wild-type hUbb and the frame-shifted version hUbb(+1) were expressed in transgenic Drosophila using the doxycycline-regulated system. Misframed proteins were abundantly produced, both from the transgenes and from endogenous Drosophila ubiquitin-encoding genes, and their abundance increased during aging in whole-fly extracts. Over-expression of wild-type hUbb, but not hUbb(+1), was toxic during fly development. In contrast, when over-expressed specifically in adult flies, hUbb(+1) caused small decreases in life span, whereas hUbb was associated with small increases, preferentially in males. The data suggest that MM occurs in Drosophila and that the resultant misframed proteins accumulate with age. MM of the ubiquitin gene can produce alternative ubiquitin gene products with different and sometimes opposing phenotypic effects.
|Role of acyl-coenzyme a: cholesterol acyltransferase activity in the processing of the amyloid precursor protein.|
Puglielli, Luigi, et al.
J. Mol. Neurosci., 24: 93-6 (2004)
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory deficit, cognitive impairment, and personality changes accompanied by specific structural abnormalities in the brain. Deposition of amyloid-beta (Abeta) peptide into senile plaques is a consistent feature of the brains of patients affected by AD. Studies with both animal and cellular models of AD have shown that cholesterol homeostasis and distribution regulate Abeta generation. We have provided genetic, biochemical, and metabolic evidence that implicates intracellular cholesterol distribution, rather than total cholesterol levels, in the regulation of Abeta generation. This minireview focuses on the role of acyl-coenzyme A: cholesterol acyltransferase activity (ACAT) in Abeta generation. In genetically mutant cell lines that overproduce cholesterol but cannot synthesize cholesteryl esters (CEs) because of deficient ACAT activity, Abeta production is almost completely inhibited. Acyl-coenzyme A: cholesterol acyltransferase activity (ACAT) inhibitors, currently being developed for the treatment and prevention of atherosclerosis, reduce CE levels and Abeta generation by up to 50% in cell culture models of AD. Future mechanistic and transgenic animal studies are needed to evaluate the potential use of ACAT inhibitors in the therapeutic treatment or prevention of AD.
|Structure and function of amyloid in Alzheimer's disease.|
Morgan, Carlos, et al.
Prog. Neurobiol., 74: 323-49 (2004)
This review is focused on the structure and function of Alzheimer's amyloid deposits. Amyloid formation is a process in which normal well-folded cellular proteins undergo a self-assembly process that leads to the formation of large and ordered protein structures. Amyloid deposition, oligomerization, and higher order polymerization, and the structure adopted by these assemblies, as well as their functional relationship with cell biology are underscored. Numerous efforts have been directed to elucidate these issues and their relation with senile dementia. Significant advances made in the last decade in amyloid structure, dynamics and cell biology are summarized and discussed. The mechanism of amyloid neurotoxicity is discussed with emphasis on the Wnt signaling pathway. This review is focused on Alzheimer's amyloid fibrils in general and has been divided into two parts dealing with the structure and function of amyloid.
|Distinct presenilin-dependent and presenilin-independent gamma-secretases are responsible for total cellular Abeta production.|
Wilson, Christina A, et al.
J. Neurosci. Res., 74: 361-9 (2003)
gamma-Secretase is the second of two proteolytic enzymes involved in the liberation of the beta-amyloid peptide (Abeta) from the amyloid precursor protein (APP). gamma-Secretase cleavage occurs at several intracellular sites, including the Golgi network and the endoplasmic reticulum/intermediate compartment (ER/IC) to produce multiple forms of the Abeta peptide that can be either secreted from the cell or remain intracellular. To date, most evidence has suggested that members of the presenilin protein family are required for gamma-secretase activity. Although it seems that presenilins are indeed necessary for the production of most secreted and intracellular Abeta particularly that generated in downstream organelles, it was shown recently that a presenilin-independent gamma-secretase is active in the ER/IC and is responsible for the production of a portion of intracellular Abeta42. We discuss the implications of this finding for the understanding of presenilin biology and speculate on the putative identity of the presenilin-independent cleavage activity.