It has been demonstrated that chaperones/co-chaperones interact with PD-related proteins and regulate their function in PD. HSP70, HSP90 and small heat shock proteins can prevent neurodegeneration by regulating α-syn misfolding, oligomerization and aggregation.Oct
Parkin, PINK1 and DJ-1 are PD-related proteins which are associated with mitochondrial function. Molecular chaperones regulate mitochondrial function and protein homeostasis by interacting with these PD-related proteins. This review discusses critical molecular chaperones/co-chaperones and PD-related proteins which contribute to the pathogenesis of PD, hoping to provide new molecular targets for therapeutic interventions to thwart the disease progression instead of only bringing symptomatic relief. Moreover, appreciating the critical role of chaperones in PD can also help us screen efficient biomarkers to identify PD at an early stage.
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Summary: Chaperone proteins in human cells dynamically interact with the protein alpha-Synuclein, which is strongly associated with Parkinson's disease. A disturbed relationship to these 'bodyguards' leads to cell damage and the formation of Lewy bodies typical for Parkinson's disease
chaperones as central mediators in the formation, de-aggregation and degradation of the aggregates. Altered expression and function of chaperones is associated with many neurodegenerative diseases including Parkinson’s disease. Several studies indicate that chaperones are at the center of the cause and effect cycle of this disease. An overview of the various chaperones that are associated with homeostasis of Parkinson’s disease-related proteins and their role in pathogenicity will be discussed in this review.
mitochondrial Rhomboid protease may be a causative factor in the disease. Two significant outcomes may result from the proposed research. First, a diagnostic tool, Rhomboid cleavage, may be discovered as a way to detect early signs of the disease. Second, regulating Rhomboid activity may be a way to prevent neuronal cell death to treat disease progression
The work that we will do over the next year with the Rhomboid protease will allow us to understand better a potential route of cell death, and with that, a way to design ways to prevent neurons from dying. Proteases are excellent drug targets and numerous small molecule libraries exist that can be tested for therapeutic efficacy.
I'm not at my normal computer... but there have been TWO studies released since August, 2022 ... that there is a NON-invasive... CHEAP... FAST ... way to nearly 100% diagnose... by a 3 minute test that is almost 100% accurate in diagnosing PD!
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my stupid stupid neurologist, MDS -- did NOT know about these new tests!
disorders. Cellular molecular chaperones, which are ubiquitous, stress-induced proteins, and newly found chemical and pharmacological chaperones have been found to be effective in preventing misfolding of different disease-causing proteins, essentially reducing the severity of several neurodegenerative disorders and many other protein-misfolding diseases. In this review, we discuss the probable mechanisms of several protein-misfolding diseases in humans, as well as therapeutic approaches for countering them. The role of molecular, chemical and pharmacological chaperones in suppressing the effect of protein misfolding-induced consequences in humans is explained in detail. Functional aspects of the different types of chaperones suggest their uses as potential therapeutic agents against different types of degenerative diseases, including neurodegenerative disorders.
Proteins that are not able to achieve the native state, due either to an unwanted mutation in their amino acid sequence or simply because of an error in the folding process, are recognized as misfolded and subsequently targeted to a degradation pathway. This is referred to as a protein ‘quality control’ (QC) system and is composed of two components: molecular chaperones and the ubiquitin proteasome system (UPS) [[4]]. The QC system plays a critical role in cell function and survival. A special class of chaperone, for example, calnexin, forms part of the ‘quality control monitors’ that recognize and target abnormally folded proteins for rapid degradation [[5]]. One class of QC chaperone associated with the endoplasmic reticulum (ER), e.g. calnexin and calreticulin, BiP and ERp 57 [[6]], is able to recognize misfolded proteins and help their retention in the ER, allowing only correctly folded proteins to reach the cytosol [[5]]. One very strong and crucial aspect of QC in the cell is the ubiquitin proteasome pathway (UPP). Studies suggest that disturbance in or impairment of the UPP, which may be induced by the accumulation of misfolded proteins in the ER or loss of function of the enzymes involved in the ubiquitin conjugation and deconjugation pathway, leads to altered UPS function, which positively affects the accumulation of protein aggregates in the cell [[4]]. The formation of oligomers and aggregates occurs in the cell when a critical concentration of misfolded protein is reached. Aggregated proteins inside the cell often lead to the formation of an amyloid-like structure, which eventually causes different types of degenerative
protein-misfolding disorders, an error in folding occurs because of either an undesirable mutation in the polypeptide
****mutation in the polypeptide****
diseases. Reduction in the intracellular level of chaperones results in an increase in abnormally folded proteins inside the cell [[5]]. Therefore, toxicity in different neurodegenerative disorders may result from an imbalance between normal chaperone capacity and the production of misfolded protein species. Increased chaperone expression can suppress the neurotoxicity caused by protein misfolding,
*****increasing chaperone activity can reduce the misfolded priteins***
some human disorders, protein misfolding takes place due to repetition of glutamine in the polypeptide chain
****Molecular chaperones can prevent protein misfolding and aggregation****
Molecular chaperones are composed of several distinct classes of sequence-conserved proteins, most of which are stress inducible like heat shock proteins (Hsp
I believe that they have trialed Ambroxol in the past and are trialing it once again (which is a pharmacological chaperone for increasing glucocerebrosidase activity). They have shown that this old cough medication may assist in the clearance of mis-folded proteins.
I'm not the brightest but does this mean it could be a cure, a reversal? "They have shown that this old cough medication may assist in the clearance of mis-folded proteins.2
I would not go that far. As it is another tool in the shed, so to speak.
It does assist in the Brains garbage disposal system, by increasing the clearance of waste inside brain cells. They believe that it is the build up of waste / damaged proteins, etc, that leads to Parkinson’s and the more build-up of damaging proteins in the brain, the worse the neurological disorders progresses.
Nero-degenerative diseases such as Alzheimer’s and Parkinson’s, involve the build-up of misfolded proteins within and around nerve cells, which is exacerbated because of a defective waste disposal system.
Glucocerebrosidase or GCase, (in its abbreviated form) is active inside small structures called lysosomes, clearing waste from cells; breaking down toxic substances, digesting bacteria that invade the cell, and recycling worn-out cell components. Individuals with Parkinson’s have very low levels of GCase function.
GCase is transported to lysosomes where the lysosome then absorbs the GCase enzyme where it performs its job of waste processing. However, in Parkinsons disease patients, they have low levels of the GCase enzyme which does not get absorbed into the lysosome as it should. The result is that they stick to the outside preventing other proteins from getting inside. These other proteins include alpha-synuclein which is known to form toxic accumulations in the brains of people with Parkinson’s which then starts the cascade effect of accumulation of these proteins producing stress to the cells, ultimately leading to the cells dying.
The cough medication called Ambroxol has demonstrated the ability to increase GCase levels and improve lysosome function, and rescue cells.
The Phase 2 Trial was not design to see improvement in patients but to establish further the proof of concept that the cough medication (Ambroxol) is effective at crossing the blood-brain barrier, and it achieved a good level of penetrance into the brain, and there was a 35% increase overall in levels of the GCase enzyme levels.
So if their theory is correct, then increasing the GCase enzyme in the brain, should assist in the clearance of unwanted misfolded proteins, and allow the brains garbage system to function as it should.
Not a cure, but a step in the right direction and as I stated in the outset, another tool to arrest the decline in patients.
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