The life cycle of a protein
After synthesis, proteins require correct folding and trafficking to the correct cellular location. Components of the cell's proteostasis machinery mediate these functions, as well as detoxifying damaged and misfolded proteins. Pathways that regulate aging can modulate many aspects of proteostasis, through transcription factors such as DAF-16 and HSF-1, and effector molecules such as the kinase mTOR.
Clinical, biochemical and molecular
phenotype of congenital disorders of glycosylation: long-term follow-up
Protein-misfolding diseases and chaperone-based therapeutic approaches
In almost all protein-misfolding disorders, an error in folding occurs because of either an undesirable mutation in the polypeptide or, in a few cases, some less known reason. The harmful effect of the misfolded protein may be due to: (a) loss of function, as observed in cystic fibrosis (CF) and a1 antitrypsin deficiency; or (b) deleterious ‘gain of function’ as seen in many neuro-degenerative diseases such as Alzheimer’s disease (AD), Parkinson’s disease (PD) and Huntington’s disease (HD), in which protein misfolding results in the formation of harmful amyloid. Protein aggregates are sometimes converted to a fibrillar structure containing a large number of inter-molecular hydrogen bonds which is highly insoluble.
These are commonly called amyloids and their accumulation occasionally results in a plaque-like structure.
Lysosomal metabolism of glycoproteins
The cytosolic/lysosomal pathway would be expected to be up-regulated under conditions in which the production of incorrectly folded or glycosylated glycoproteins is increased, for example, in l patients with congenital disorders of glycosylation type I or in cells or tissues secreting high concen-trations of glycoproteins according to physiological demand, such as the pancreas.
Glycoproteins with many different functions and cellular locations are normally turned over in lysosomes and the digestion products recycled. In conjunction with the proteasome, lysosomes contribute to the regulation of synthesis of N-linked glycoproteins. Defects in the lysosomal system disrupt these processes and lead to severe diseases, illustratting the importance of the continuous cycle of biosynthesis and degradation of glycoconjugates to cellular function and adaptability. In the extreme lysosomes are involved in both necrosis and apoptosis of cells.
The evolutionary consequences of erroneous protein synthesis
Protein-misfolding diseases and chaperone-based therapeutic approaches
From the discussion on the mechanisms of different protein misfolding disorders, it is clear that a nascent polypeptide chain can become misfolded due to a specific gene mutation, which takes place in almost all familial neurodegener-ative diseases, or a matured native protein can also achieve a misfolded conformation inside the cell, an example is the cause of prion disease. The fates of these mis-folded proteins in various disorders are different, in one class of diseases misfolded proteins interact further with each other through intermolecular interaction and form structured aggregates thus gaining toxicity. Neurodegenerative disorders are good examples of this specific l pathway. It might be that the proteasome pathway is not efficient enough to degrade these misfolded proteins prior to aggregation because of impairment of the UPS. In another case, misfolded proteins are directed to the UPP with the help of many other chaperones in addition to ubiquitins, and are consequently degraded by the action of proteasome. Hence these proteins l cannot be secreted from the ER, but are degraded and their disappearance from the specific site inside the cell where they function l causes disease. Good examples of this are CF and a-antitrypsin deficiency disorder.
Targeted delivery of proteins across
the blood–brain barrier
Stability of mRNA/Cationic Lipid Lipoplexes in Human and Rat Cerebrospinal Fluid: Methods and Evidence for Nonviral mRNA Gene Delivery to the Central Nervous System
Congenital Disorders of Glycosylation (CDG) from a Neurological Perspective
Prions and Protein Misfolding
https://youtu.be/Chs7ixRstQk
Thank you for your well researched and referenced articles.