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Fat
Published in Christopher Cumo, Ancestral Diets and Nutrition, 2020
Besides these flaws, Perlmutter and Taubes unrealistically supposed that hunter-gatherers loaded up on fat from wild animals.23 They have fat, though the amount varied with their fortunes. During flush times, animals ate their fill and accumulated fat, but scarcity made them lean and hungry. Chapter 3 introduced the phenomenon of rabbit starvation, a type of protein toxicity, whereby people died from eating exceptionally lean animals like rabbits (Oryctolagus cuniculus).24 Such game furnished insufficient fat, carbohydrates, vitamins, minerals, or their combination. Rabbit starvation implies that wild animals were leaner than Perlmutter imagined, especially during privation.
Exploration of Nanonutraceuticals in Neurodegenerative Diseases
Published in Raj K. Keservani, Anil K. Sharma, Rajesh K. Kesharwani, Nutraceuticals and Dietary Supplements, 2020
Swati Pund, Amita Joshi, Vandana Patravale
Protein toxicity is a unifying feature of both sporadic and familial cases of neurodegeneration. Neuronal degeneration causes immense cellular stress and results in the formation of stress granules. Electrostatic interactions between proteins facilitate liquid–liquid phase separation causing formation of stress granules (Chung et al., 2018). Two leading neuropathological changes of AD are the neurofibrillary tangles made of paired helical filaments containing the microtubule-associated protein, tubulin-associated unit (Tau) accumulating in neuronal perikarya and extracellular diffuse amyloid deposits containing amyloid peptide-forming neuritic senile plaques (Bloom, 2014; Giacobini and Gold, 2017). Inhibition of tau phosphorylation, proteolysis and aggregation, promotion of intra- and extracellular tau clearance, and stabilization of microtubules are the pathways to be explored for development of new therapeutics. Amyloid β (Aβ) peptides are 39–43 amino acid residue peptides derived from the sequential proteolytic enzymatic action of β-secretase and γ-secretase on transmembrane amyloid precursor protein. Aβ deposition and diffused plaque formation causes local microglial activation, cytokine release, reactive astrocytosis, and a multiprotein inflammatory response.
Protein Subunit Vaccines and Recombinant DNA Technology
Published in F. Y. Liew, Vaccination Strategies of Tropical Diseases, 2017
Inevitably, high expression of recombinant proteins, whether they be candidate vaccine antigens or otherwise, can lead to some problems. There are essentially four key problem areas: (1) plasmid stability, both during storage and expression, (2) protein turnover, i.e., the stability, both in vivo and in vitro of the protein itself, (3) compatibility of the gene and host (a rather poorly defined area of accuracy of translation, ribosome pausing and aggregation), and (4) recombinant protein toxicity to both the host and the external environment.
The contribution of C. elegans neurogenetics to understanding neurodegenerative diseases
Published in Journal of Neurogenetics, 2020
Joseph J. H. Liang, Issa A. McKinnon, Catharine H. Rankin
HD is but just one member of a family of diseases sharing toxic polyglutamine repeats. To date, including HD a total of nine polyQ neurodegenerative disorders have been described (Fan et al., 2014). The Morimoto group established a model aimed towards a more general understanding of polyQ repeat toxicity by expressing short (Q-19) and long (Q-82) polyQ-GFP fusion proteins in C. elegans body wall muscle cells and neurons (Brignull, Moore, Tang, & Morimoto, 2006; Satyal et al., 2000). Further work with this model showed that there is a narrow threshold of polyQ repeat size for induction of aggregation and toxicity: expression of anything more than 35–40 polyQ repeats resulted in the aggregate formation and signs of cellular stress (expression of heat shock proteins; Morley, Brignull, Weyers, & Morimoto, 2002). Additionally, by using this model to observe physiological changes the group showed that the formation of polyQ aggregates generally disrupted protein homeostasis (Gidalevitz, Ben-Zvi, Ho, Brignull, & Morimoto, 2006). Results from these studies support a general ‘chaperone depletion’ hypothesis proposing that the aggregating protein toxicity comes from competition for limited components of the protein homeostasis machinery. Indeed, an RNAi screen was able to identify a large set of protein folding or protein degradation genes that increased polyQ aggregation when their expression was knocked down (Nollen et al., 2004).
Tryptophan 2,3-dioxygenase, a novel therapeutic target for Parkinson’s disease
Published in Expert Opinion on Therapeutic Targets, 2021
Fanni Annamária Boros, László Vécsei
For a better understanding of TDO involvement in the pathomechanism of PD, van der Goot et al. used a Caenorhabditis elegans model [65]. In this model the detrimental effects of α-syn accumulation are indicated by age-related progressive decline in the motility of the animals. TDO knockdown decreased α-syn toxicity and similarly toxicity of other aggregation-prone proteins such as β-amyloid peptide and polyglutamine, suggesting a general role of TDO in the process [65]. Genetic inhibition of TDO also extended both the chronological lifespan and the reproductive span of the animals and suppressed age-related motility decline. Neither inactivation of downstream KP enzymes nor feeding the animals with KYN protected against α-syn toxicity, suggesting that variations of KP metabolite levels are not responsible for the protective effects of TDO inhibition [65]. On the contrary, feeding the worms with increasing amounts of Trp led to a dose-dependent suppression of α-syn toxicity. The findings of van der Goot and colleagues point to a further mechanism by which the KP can affect neurodegeneration: via regulating age-related protein toxicity [65]. The data suggest that this is achieved through Trp, likely by the amino acid itself or its derivatives acting on other signaling molecules and pathways involved in protein toxicity. Another mechanism by which Trp can be protective was outlined above: blocking 3-HK toxicity by competing for transporter to cellular uptake [59]. These findings indicate that modulation of Trp levels via inhibition of TDO could help by delaying the age-related decline of protein homeostasis thus could be a valuable tool in the treatment of aging-associated neurodegenerative disorders, such as PD.
Identification and characterization of an IgG sequence variant with an 11 kDa heavy chain C-terminal extension using a combination of mass spectrometry and high-throughput sequencing analysis
Published in mAbs, 2019
Claire Harris, Weichen Xu, Luigi Grassi, Chunlei Wang, Abigail Markle, Colin Hardman, Richard Stevens, Guillermo Miro-Quesada, Diane Hatton, Jihong Wang
For mAb therapeutics, the impact of a sequence variant on potency, pharmacokinetics (PK) and patient safety largely depends on the location, the nature of the variant and the mechanism of action of the therapeutic. Mutations at the receptor binding sequence have been reported to have various degrees of positive or negative effects on receptor binding affinity.42-44 Mutations in the Fc region can affect antibody PK,45,46 possibly by altering binding to the neonatal Fc receptor (FcRn) or protein structure. Sequence variants also pose potential patient safety concerns. Protein therapeutics with sequence variants, even single amino acid mutations, can potentially impact immunogenicity through misfolded protein toxicity, such as aggregation and interference with membranes. The risk increases with the increase in absolute protein concentration.3,47 Therefore, it is important to identify, characterize, and quantify any sequence variants to evaluate the impact on efficacy, PK, and risk to patients. For mAb-A, the potency of the monomer and the shoulder fractions was found to be comparable using a bioassay that is directly linked to mAb-A’s mechanism of action (data not shown). Therefore, it can be concluded that this 11 kDa sequence variant should have no impact on the biological activity of mAb-A. Since the extension is found at the C-terminus of the heavy chain, a substantial distance from the FcRn binding site, it is therefore unlikely to affect PK. Furthermore, with the Fc extension being identified as the light chain constant region, the immunogenicity and safety risks are considered low. Currently, available Phase 1 and 2 data indicate that this molecule has a very low incidence of anti-drug antibodies and an acceptable safety profile (data not shown).