Misframed Proteins and Neurodegeneration: A Novel View on Alzheimer's and Parkinson's Diseases
ABSTRACT Sporadic forms of Alzheimer's and Parkinson's diseases are the most frequent forms of their kind. Together with Huntington's disease, they belong to the so called 'conformational diseases' as they share a common feature in the accumulation of insoluble protein deposits. In this review, we focus on the significance of the ubiquitin-proteasome system in conformational diseases and the possible consequences due to the accumulation of aberrant proteins. In all forms of Alzheimer's and Huntington's diseases, but not in Parkinson's disease, we have shown the presence of misframed proteins such as misframed ubiquitin (UBB(+1)) of which we have determined the functional relevance in vitro and in vivo.Misframed proteins are the result of the inaccurate transcription of monotonic sequences in the genome and their subsequent translation. This process has been called 'molecular misreading'. In the present review, we will discuss the present state of the art with regard to UBB(+1) and amyloid precursor protein APP(+1).
Conference Paper: Performance of multichannel autoregressive spectral estimators[Show abstract] [Hide abstract]
ABSTRACT: This paper compares and contrasts the performance of multichannel periodogram and autoregressive spectrum analysis techniques periodogram when processing sunspot and world air temperature data, a first order autoregressive process, and an artificial data set of sinusoids in colored noise. It is shown that the high resolution benefit of autoregressive analysis must be tempered by an awareness of a severe feed across effect among the autospectral autoregressive estimates that may prevent multichannel autoregressive spectral estimation from being a viable spectral estimation approach. The feed across effect manifests itself as very sharp spikes in the autospectrum where there should be no spectral energy. The cause is known to be inexact pole-zero cancellation in the autoregressive coeffieient matrix estimates. Performing single channel autoregressive spectral estimates will provide indications of where the feed across effect is occurring. The astronomical literature has applied these multichannel autoregressive techniques to correlate sunspot activity with terrestrial activity such as tides, earth rotation variations, air temperature variations, and drought cycles. High correlation has alledgedly been found. However, the findings of the literature is now in doubt because this author believes that the astrophysical researchers were misled by the feed across anomaly. This paper also serves to correct some errors reported on examples in reference .Acoustics, Speech, and Signal Processing, IEEE International Conference on ICASSP '86.; 05/1986
- [Show abstract] [Hide abstract]
ABSTRACT: The etiology of the sporadic form of Alzheimer's disease (AD) remains largely unknown. Recent evidence has suggested that gene-environment interactions (GxE) may play a crucial role in its development and progression. Whereas various susceptibility loci have been identified, like the apolipoprotein E4 allele, these cannot fully explain the increasing prevalence of AD observed with aging. In addition to such genetic risk factors, various environmental factors have been proposed to alter the risk of developing AD as well as to affect the rate of cognitive decline in AD patients. Nevertheless, aside from the independent effects of genetic and environmental risk factors, their synergistic participation in increasing the risk of developing AD has been sparsely investigated, even though evidence points towards such a direction. Advances in the genetic manipulation of mice, modeling various aspects of the AD pathology, have provided an excellent tool to dissect the effects of genes, environment, and their interactions. In this paper we present several environmental factors implicated in the etiology of AD that have been tested in transgenic animal models of the disease. The focus lies on the concept of GxE and its importance in a multifactorial disease like AD. Additionally, possible mediating mechanisms and future challenges are discussed.10/2010; 2010. DOI:10.4061/2010/859101
- [Show abstract] [Hide abstract]
ABSTRACT: 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.Aging 03/2011; 3(3):237-61. · 4.89 Impact Factor