A quantitative model of human neurodegenerative diseases involving protein aggregation

Abstract

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Side-by-side comparison of Notch- and C83 binding to γ-secretase in a complete membrane model at physiological temperature

“…4 This failure can be due to several reasons: one is that the amyloid hypothesis is incorrect or should be supplemented, for example by accounting for metabolic and inammatory pathways. 6,7,51,52 Another is that Ab is involved in AD but cannot be reduced to this role indiscriminately as it serves important functions in the brain. 53,54 A third is that the amyloid hypothesis is correct but that inhibition of g-secretase prevents the cleavage of substrates such as Notch.…”

Survival of the cheapest: how proteome cost minimization drives evolution

“…The mechanistic basis for the theory is that (i) protein degradation increases many-fold with the lack of structure and partial unfolding in protein copies (Gsponer et al ., 2008) and (ii) the cost of protein turnover is more than half of total metabolic costs in growing microorganisms (Harold, 1987), and at least 20% in humans (Waterlow, 1995). Accordingly, any increase in these costs reduces the energy available for other energy-demanding processes, notably reproduction (fitness) of microorganisms (Dasmeh and Kepp, 2017) and cell signaling (cognition) in higher organisms (Kepp, 2019). One of many implications of the theory is that selection against misfolded proteins and toxicity of misfolding proteins measured in cell viability assays is not due to a specific toxic molecular mode of action as widely assumed, but to the generic adenosine triphosphate (ATP) burden of turning over the misfolded proteins within the cell .…”

“…An implication of this is that reduced cell viability in assays of overexpressed misfolding proteins, often used as models of neurodegenerative disease, may in fact reflect energy deficits as described by PCM theory. If so, misfolded proteins are generally not toxic by a specific mode of action (such as membrane pore formation or seeding of misfolding leading to loss of function) but rather because of the ATP costs (Kepp, 2019).…”

“…Evidence for compensatory expression is well-known, a dramatic example being homozygous sickle cell disease (Table 3), where dysfunctional, instable hemoglobin mutants cause a doubling of protein turnover and degradation in patients and a 20% increase in total resting metabolism (Badaloo et al ., 1989). Considerations of loss and gain of function mutations associated with other diseases may be viewed in this light (Kepp, 2015, 2019).…”

Computational analysis of Alzheimer-causing mutations in amyloid precursor protein and presenilin 1

“…We hypothesize here that the pathogenic APP and PS1 mutations work in one of two ways: either by decreasing the binding affinity of APP-C99 to γ-secretase (the enzyme-substrate complex) or by generally decreasing the stability of the compact membrane protein, as has been hypothesized from sequence-based computations [28]; such stability loss may lead both to loss of function of the protein [31,32], as well as gain of toxicity by elevating the cost of protein turnover of γ-secretase [33]. To explore these two options we need to investigate as many mutations as possible, we need the structures of the complex and enzyme and substrate alone, and we need control data sets of mutations that are not pathogenic.…”