Disaggregases as the Basis for Therapies to Remove Amyloids
A few proteins in the body are capable of misfolding or becoming otherwise altered in ways that encourage other molecules of the same protein to do the same. They can spread throughout a tissue and the body, given time, forming aggregates that precipitate into solid clumps and fibrils, surrounded by a halo of toxic biochemistry that harms cells. This is an age-related problem, likely because the systems of maintenance and recycling responsible for clearing aggregates falter with age, a victim of rising levels of molecular damage and the maladaptive reactions to that damage.
Amyloid-β, associated with Alzheimer's disease, is likely the most well studied of the amyloids, with transthyretin amyloid a close second. In the case of amyloid-β, immunotherapies have proven themselves capable of clearing this molecular waste, though without achieving patient benefits as a result. For transthyretin amyloid, existing therapies slow the aggregation process. A few other approaches that clear existing aggregates are in development but either stalled (CPHPC) or not moving forward as fast as we'd like (catabodies).
In today's open access paper, researchers discuss disaggregases as a basis for the clearance of amyloids. Disaggregases are a broad class of molecules capable of breaking apart amyloid aggregates. Some exist in the human body, well known parts of cellular stress response systems, some might be mined from other species. It is an interesting topic, and not that well explored as an approach to anti-amyloid therapies.
Molecular mechanisms of amyloid disaggregation
Cellular deregulation of amyloid formation is implicated in many neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), Prion disease (PrD), and diseases affecting other parts of the body such as cataracts, Type II Diabetes, and Corneal Dystrophy (CD). Fifty different proteins or peptides involved in such amyloid aggregation disorders are structurally and functionally characterized. Typically amyloid fibrils are generated from highly amyloidogenic peptide regions of a protein as the result of protein misfolding, genetic mutations, or undesired proteolytic cleavage of that protein.
However, not all amyloid fibril formation results in detrimental diseases while some may be important to fulfil a biological function and take place in well-modulated and highly contingent condition. In some cases, functional amyloids are controlled by a balance between peptide production and clearance of amyloids, reduction in the production of oligomeric seeds, minimizing interaction of oligomeric seeds with other aggregation-prone proteins via compartmentalization and the presence of an inherent disaggregation mechanism. Understanding why certain amyloids are toxic while others are biologically important may reveal important information on the function of these amyloids or develop novel treatment avenues in amyloid associated diseases.
In order to remove toxic amyloid build-up in the cell during cellular stress, some protozoans such as yeasts are equipped with molecular machines capable of disaggregating diverse amyloid and nonamyloid structures. In yeast, several types of heat shock proteins (HSPs) are discovered to work together to form disaggregation machinery. This machinery reduces the toxic amyloid species present in the cell and restores the native function of the protein buried in the amyloids via an amyloid disaggregation process. Metazoans such as mammals might experience less cellular stress resulting in the rapid build-up of toxic amyloid in the intracellular environment but are susceptible to accumulation of both intracellular and extracellular amyloids in various pathological conditions. To disaggregate these toxic amyloids in the extracellular environment, metazoans are equipped with ATP-independent chaperones such as HtrA1 and L-PGDS instead of the ATP-dependent HSPs, found in yeast. To deal with intracellular amyloids, the metazoan cells are also equipped with other types of HSPs i.e., Hsp110, Hsp70, Hsp40, and other smaller proteins from the heat shock protein families. These diverse disaggregation mechanisms evolved to reverse the formation of the toxic amyloids and survive through cellular stress and preclude amyloid-related pathogenicity.
In neurodegenerative diseases such as Alzheimer's disease, aggregates resulting from amyloidogenic peptides deposit into senile plaques which later leads to neurofibrillary tangles, synaptic dysfunction, and neuronal cell death. In each disease, a specific peptide or protein aggregates to form amyloid fibrils. There is no effective therapeutic solution that is capable of reversing the formation of these aggregates. Amyloid disaggregation seems to be a viable option where these amyloid fibrils can be broken down into non-toxic aggregates and this would possibly help to mitigate the toxic effects caused by these amyloid fibrils. In this review, we mainly focus of the disaggregation and the remodulation of the preformed fibrils into smaller molecular weight species by different disaggregating agents instead of the inhibition of fibril formation or aggregation. Many protein disaggregases have shown promising results in in vitro studies where pathogenic amyloids fibrils are solubilized through the action of these disaggregases. These studies will be discussed in this review to showcase the potential of using amyloid disaggregation as a treatment for several neurodegenerative diseases.
Hi there! Just a 2 cents.
The trick is to activate the autophagy/proteasome system, forcing autophagy, forces residue, aggregate, amyloid clearing...now, autophagy is not something to do every second; it is costly and toxic at certain activity/length of time; it is a 'fail-safe' mechanism to clear out the accumulating gunk, required for that; but cannot be 'overworked' neither; like overworking a garbage truck to 'overloaded' and 'crunched' (overtime); until it explodes...with age, as you said, the proteasome, autophagosome, lysosome get filled up (full/faster) than being emptied; hence, unbalance/dysfunction will happen because 'Clogging Up'. Same thing, with atherosclerosis, laddening in oxidized LDL/dead macrophages lapping-it-up and 'choking' the giant arterty...becoming a 'skrining pipe hole'...filled with gunk cholesterol plaques -
until, it's Blocked/totally filled and blood does not pass anymore (oxygen lack/ischemia; plaque rupture, clot formation, death from clot jamming/blocking - Too - artery; no more blood flow); with amyloid it's these (amyloid) plaques (instead of ldl cholesterol plaques); that 'take the place' on the brain matter (making the brain like a swisscheese with holes - with beta-amyloid/tau plaques in them)... kind of like, also, cancer....cancerous tumour filling up - taking the place - of the healthy space/cells; and 'replace' the whole thing; until, you are cancer filled...it seems a lot of 'deposition/depots/residues/junk/gunk accumulating' and not just taht 'taking the space', filling up, and 'replacing' the healthy (before) space...if only we had better 'emptying' systems..error-free..
but error-free, does not exist, because perfection does not exist and entropy does (exist); or as the saying goes : 'sht...happens'...in simple organisms, easy peasy, more error-free; not complex being; like humans; Prone to so many random errors; mutations et.c..it's why the smallest/simplest organism get *mmortality...while complex organisms, get mortality...
too hard to keep it error-free; too complex, so evolution makes 'hacks' and adaptions to circumvent an exponential/Ever Complex/Complicating System(s), in complex organisms - in other words; Bound To Fail (at some point, some place, some time, by 'some loose part' or 'some leak' in the ever more complicated fig. cogwheels). It's like a fig. (monkey) wrench thrown in them; by a ... monkey (daily).
They say: ''An apple a day, keeps the doctor away''.
But, it's actually: ''A carrot a day, keeps the doctor away - for good''.
It was shown that vitamin A, or (from) Carotenoids, (from carrot, and other veggies or fruits containing them); protect the brain against dementia, alzheimer's, parkinson's and just general forgetfulness/slow-mo-ness (brain haze/fog/slowing); Beta-carotene, lycopene, lutein,...these carotenoids had strong impact, and increase also vitamin A - Retinol, Retinoids, Retinoic Acid levels; which increase vision - eyesight; they say, a carrot makes one 'see better; and it's clear (pun intended) why; crystal clear; like the crystal in your eyes; the eye retina is full of retinoids;
and they protect the vision (Against vision loss/blindness..cataract formation...Scavenge ROS from excess UVs in the day time damaging/lipid-membrane PUFA-oxidizing the eye retina);; not only that;
Supercentenarians and centenarians where found to have Higher Levels of Brain Carotenoids; not just the eyes....elsewhere...the brain. They hhad high levels of B-carrotenoids, Lycopene (tomatoes), lutein...and the ones that retained their vision - had higher levels of Vitamin A (retinol/retinoid); evidently, also, higher levels of these carotenoids - in their eyes.
Vit. A, Retinoic Acid, retinol/retinoid, trans-retinol...etc...Vitamin A, in large umbrella term, is capable of 'remorphologizing'; it was found that Vit.A/Retinoic pathway controls organ morphology and stem cell-ness; meaning it reprogramms differentiated cells to undifferentiated states/cells; thus, it returns to a stemcell state; for example, birds formation of skeletal/wings - is controlled by the Vitamin A / REtinoic acid pathway...during gestation...same thing, for, geckos and other lizards that 'regrow limbs'; they use the retinoic pathway to rebuild intact the cut/lost limbs...thus, Vitamin A controls the natural stemness/differentiation potential of cells;
while carrotenoids; quench radicals; especially, lycopene and lutein; they protect against brain cell mitomembrane lipoperoxidation...hence, keep neurons alive; and Also; the retinoic pathway was foudn - to Inhibit the Amyloid Pathway - Directy; meaning, The Genes Responsible for Amyloid Formation (beta-amylo/tau/ceroid/drusen/parkin...and the whole junk) in brain and whole body were abrogated/diminished when the retinoic/vit.a pathway was taken...I think it is possible that this pathway also acts on the autophagous/autoevacuating pathways;; so it works in tandem;
Thus, vit. a and combined with a 'Autophagy Activating' method...will yeild best result to keep your memory and intelligence (neurons/functions); and will remove the toxic crap that accumulates in brain and everywhere else; plus, deep sleep - REM/deep sleep is Crucial; the circadian clock is responsible for 'junk shunting'....your brain does cleaning while sleeping....so make sure get best sleep and best chance of preserving brain...best sleep is characterized as 'monotonous sleep' - the same every night - the same 7 hours of sleep - every - night; 7 hours is gold mean (for adults in general); above 7 hours can mean fatigue or sleep membrane/choking apnea (deadly, die in sleep); under 7 will mean insomnia and possibly 'waking up' breaking the 7 hours continous block;
(ant that is badl; you don'T want to wake up/chunk your sleep in little bits cumulating seven hours (studies said that waking up did not reduce mortality...but, I think it's not best, you want to avoid waking up - we are not like dolphins who can sleep 3 hours and wake up 50 times...we need 7 hours straight for the Brain to do its cleaning/neuron-recalibrating job - while we 'dream' - dreams are part of the brain cleaning strategy); which means waking up and going to sleep many times in one night; you shouldn't, you should go to sleep - sleep entire night - wake up in the morning; all in 1 shot/full-block sleep);
Centenarians - had a common thing - they slept 'monotonous hours'...meaning Always the same thing, every night; their 7 hours, same hour of sleep; at 12:00AM - in the bed...each night.
Sleep is crucial to become a centenarian, because the Circadian Clock is a controller of many night/daily genes...and controls, also, the arrival of diseases - the circadian clock is, you could say, a sort of (sleep) surrogate of the epigenetic clock. They don'T measure the same thing; but they communicate and work in tandem; epigenetics - are Behind - the circadian clock; each it, it entrained by the diurnal and nocturnal shifts..in genes.. activity/expression...
At night, we have the 'night genes' system..and in day time the 'daytime genes'....system..
Remember, sleep protects brain, protects against dementia, alhzheimer'S...etc....but it'S not enough; we age and we still sleep; so we must compensate elsewhere...like having Centenarians higher levels of Carotenoids (brain carotenoids; they are made Naturally); Centenarians and Supercentenarians forensic examination of their brains showed that they had 'young/youth' like brains...of someone younger (we know that on average they were 8 years younger epigenetically than avg. population); that their brains 'retained' youth features...this means 'Neoteny/neotenous' features...keeping brains in plasticizing and neuron synthesis (BDNF); they had less 'brain matter loss' (gray and white matter); thus, less Brain Pruning; that happens with age to all people; our brain become a shrinking/dryingup prune...full of holes and filled with amyloids....-> dementia, retardation, slowness, can't 'quick-think' anymore, can't memorize anything (pre-alzheimer's/amnesia), forget everything, even stuff that happened 5 second ago (like where your keys were or what you 'just said 5 secs ago').....
Another one, is hot/cold showers....they activate the proteasome (and Heat Shock Response (HSPs) Heat Shock Proteins -> they activate the autophagy); same with other 'mid stresses' and other 'hormesis' stresses; just slight stresses are good; above that, toxic...too much autophagy toxic; there are several studies that show that Unhealthy people can die of excess autophagy activation; autophagy/proteasome are Inhibited to relieve the inflammation in their case;
so, autophagy/proteasome activation is mostly benefitial, when Already Healthy...& only Dosed.
otherwise, when sick, like a Double-Edged Sword..it can turn bad against you...like the immune system.
As the famous botanist, protobiologist, herbalist, apothecarist, apiculturist, agriculturist, said:
''The dose makes the poison, or the cure.''.
Just a 2 cents.
Great comment, CAN!