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Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
PD is a mostly sporadic disease which is likely multifactorial and heterogeneous in etiology. PD occurs due to a complex interaction among genetic, environmental, and other individual factors. PD is not one condition with a single cause for all patients, but is rather a downstream clinical syndrome resulting from different types of insults to the substantia nigra (e.g. hereditary, toxic, infectious, age-related). Despite continued expansion of scientific understanding, the cause of dopaminergic cell death in PD is not fully understood and probably heterogeneous and multifactorial, related to a probable self-propagating series of reactions including: Oxidative stress, reactive oxygen species production.Mitochondrial dysfunction.Excitotoxicity.A rise in intracellular free calcium.Protein aggregation.Inflammation.
Lessons to Be Learnt from Ayurveda
Published in D. Suresh Kumar, Ayurveda in the New Millennium, 2020
Prachi Garodia, Sosmitha Girisa, Varsha Rana, Ajaikumar B. Kunnumakkara, Bharat B. Aggarwal
Neurodegenerative diseases represent advanced disorders of the neurons that could cause destruction or abolish the function of the neurons (Kannappan et al. 2011). Neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease are known to have general features in cellular and molecular mechanisms that include protein aggregation and inclusion body formation (Ross and Poirier 2004). A wide range of these disorders are characterized by damage in neurons which might be a result of toxic and aggregate-prone proteins (Taylor et al. 2002). They pose a great threat to human health and have increasingly affected the elderly population in recent years (Heemels 2016).
Stress Proteins in Renal Ischemia
Published in John J. Lemasters, Constance Oliver, Cell Biology of Trauma, 2020
When mutant E. coli cells do not synthesize HSPs, extensive aggregation of all cell proteins occurs, even under normal, nonstressed conditions. If protein synthesis is inhibited, aggregation is suppressed.46 This suggests that HSPs are necessary to achieve the proper conformation required for the soluble state of most cytoplasmic proteins after translation. Beckmann et al. showed that insoluble protein-HSP aggregates formed when HeLa cells were subjected to stress.47 The stresses were heat, arsenite, and amino acid analogs. In unstressed cells, newly synthesized and nascent proteins bind transiently to HSP 70. In stressed cells, newly synthesized proteins and native proteins (unfolded by the stress) form stable, insoluble complexes with HSP 70. HSP proteins also prevented protein aggregation in another experimental system (i.e., aggregation of heterologous proteins in E. coli). Aggregation of human procollagenase in E. coli was dramatically reduced by overexpression of HSP analogs DnaK and GroEL.48
Evaluation of physicochemical and functional similarity of a new CHO derived anti-EGFR antibody P-mAb to its reference medicinal product
Published in Artificial Cells, Nanomedicine, and Biotechnology, 2022
Jitender Nandal, Kanti N. Mihooliya, Himanshu Verma, Nidhi Kalidas, Fnu Ashish, Ravi P. N. Mishra, Debendra K. Sahoo
Prevention of protein aggregation during the processing of protein-based drugs is of crucial interest. The purity and size variants of P-mAb and RMP were analysed using SDS-PAGE, SEC-HPLC, and SV-AUC. The molecular size of RMP and purified P-mAb, compared using SDS-PAGE analysis under reducing and non-reducing conditions, showed the protein bands of both molecules to be matching and no other low or high molecular weight protein bands were observed (Figure 6(A)). Analysis of purity of the purified P-mAb using SEC-HPLC found the retention time of the main peak of purified P-mAb and RMP samples to be identical (7.20 min) absence of any low molecular weight (LMW) entity though high molecular weight (HMW) aggregates were present in both the samples, % of HMW aggregates in case of RMP (0.85%) being higher in comparison to that of purified P-mAb (0.64%) (Figure 6(B)). SV-AUC, used as an orthogonal method to SEC-HPLC to further examine the presence of aggregates in the samples, also confirmed the presence of HMW aggregate in both the samples and showed the size distribution of P-mAb and RMP to be similar (Figure 6(C,D)). In conclusion, the aggregation propensity of both P-mAb and RMP was proven to be similar.
Targeting protein clearance pathways in GBA1-associated Parkinson disease
Published in Expert Opinion on Therapeutic Targets, 2022
Chase Chen, Ellen Hertz, Yu Chen, Ellen Sidransky
Studies have shown that the primary mechanisms for the degradation of mutant α-synuclein and GCase are the ALP and UPS, respectively. The enhancement of both pathways is an exciting approach to modulating protein aggregation to potentially slow disease progression. It should however be noted that the cell’s protein clearance programs are an intricate web, where enhancement of one part, may very well affect the other. The recent study by Kuo et al. showing that GBA1-mutations do not only impair macromolecular degradation specifically by lowering GCase activity, but that they also inhibit CMA degradation in general, demonstrates the wider implications of GBA1 on cellular proteostasis [36]. Efficient treatment might require simultaneous degradation of misfolded GCase and restoration of wildtype GCase, solving both a gain- and loss-of-function. Loss-of-function leading to substrate accumulation is an attractive theory, as shifts in lipid content affects α-synuclein folding. However, to date there is limited evidence supporting substrate accumulation in brains from patients with GBA1-PD, and therefore targeting proteostasis might be a more efficient therapeutic approach.
In vitro study of the mechanism of intraneuronal β-amyloid aggregation in Alzheimer’s disease
Published in Archives of Physiology and Biochemistry, 2022
Shahad Alsunusi, Taha A. Kumosani, Charles G. Glabe, Etimad A. Huwait, Said S. Moselhy
Amyloid oligomers are soluble non-monomeric structures that appear as intermediates or final products in the process of protein aggregation lacking one or more of the hallmarks of fibrillar structure. Amyloid oligomers involved in many diseases such as amyloid β, huntingtin (Htt), α-synuclein, tau and the prion protein (Reiman et al.2012). They are highly heterogeneous in size, structure, stability and morphology. Different pathways may lead to the peptide aggregation. The amyloid polypeptide is organised in a characteristic “cross β” pattern in a regular manner, in which adjacent chain segments are folded in an antiparallel manner within the fibre lattice. Other reported that the peptide chains of β-strand run perpendicular to the long fibril and the intermolecular hydrogen bonds of β-strands run parallel to the axis in a “cross β” structural pattern (Glabe 2001).