Popular Science Stories
Good Nature of the Devil: The Protein Aggregate Story
Pritam Mukherjee From the biblical "fountain of youth" to a popular mid 1900s Bengali film "Ashite Ashiona" meaning do not come to your eighties, portrays the wish of every aged and centenarians to metamorphosize to their younger self. The idea of living longer, thus far have been of keen scientific interest. With living longer, the account for living healthy has also been the prime focus of today’s aging research. The need of the hour is to commit to research to find out ways for healthy aging as the world population is becoming aged. Recent data from WHO suggests that there will be significant proportion of the global population above 65 years of age by 2050. Efficient ways are therefore needed to maintain these huge population at healthy state. Aging can be seen as the gradual decline of physical and functional ability with time. It makes the one more susceptible to diseases and death. Truly so, the number of diseases such as Cardiovascular, immuno-metabolic, neurodegenerative diseases and Cancer primarily are the diseases of old age. Scientists as for now have classified several of the hall mark features of aging. One of the crucial hallmarks is the progressive decline in maintaining proteins in a correct state and conformation so that they remain functional. Proteins are the central players of all cellular processes. It arises from a dedicated information containing entity known as gene and once they are synthesized, they assume proper conformation for their functions. After their duty is done, they are degraded. There is a policing system that keeps an eye during the synthesis, folding and degradation processes. These processes go awry during aging and as for now are considered as the main culprits for the protein misfolding, where their structures are deformed and gradually, they start aggregating which means they form clumps. These protein clumps can be toxic for the cell. Several diseases have been reported to be caused by this toxic protein aggregates such as Alzheimer's disease, Parkinson's disease, Amylotropic Lateral Sclerosis, etc. Off course, from our ongoing discussion, we might think that protein aggregation is always toxic. Recent research from across the globe suggests that this is not the case. The aggregates of protein can also be functional and perform physiological functions. These functional aggregates have been reported from simple one celled bacterium to complex mammals. To understand complex processes, we often use certain model organisms that gives us a clue what might be occurring at a bigger scenario. Caenorhabditis elegans is one such organism that has given scientists a vast amount of knowledge regarding several facets of biology. The organism serves as a premier model for aging research. The reasons being its short lifespan which is roughly 20 days, they have the characteristic aging behaviour and significant proportion of its genes have similarity with humans. There are several molecular pathways that are common between humans, and this small animal. It is worth mentioning that, the notion of aging is controlled by genes was first identified in this organism. There are several life span mutants available for this animal, that is the C. elegans which is having mutation in its genes either lives lesser or longer than its average 20 days. This has allowed scientists to pin down the molecular pathways and determinants that controls aging. One such mutant is daf-2 mutants, this are animals that have a mutation in the daf-2 gene which gives rise to a receptor that functions in monitoring insulin. This mutant animal live twice as that of animals that does not have this mutation. It was an interesting observation from the work published a group in the journal Cell, that these daf-2 mutant animals have more protein aggregation during aging. This is counterintuitive, as it is hard to believe that an animal which is living longer has more of these nuisances. Partly answered from that paper is like there are proteins in these animals that functions like a group of policemen encircling an angry mob, the aggregates to restrict them into a confined space and reduce the damage. This policing mechanism ensures that other police can do their work well who have other functions in the cell. Inside the cell there are vast number of things that goes on. To ensure that this works well, cells compartmentalize the constituents of these reactions into a membrane bound structure often called scientifically an organelle. There is a growing realization that the cell does not only consists of membrane bound organelles but also membraneless organelles. Latter are also termed as biomolecular condensates. These condensates are membraneless entities in the cell that concentrates specific biomolecules. The typical examples are nucleolus, cajal bodies, nuclear speckles, paraspeckles, stress granules, P granules, P bodies etc. These all condensates have different functions ranging from cell signalling, ribosome synthesis, body patterning, mRNA metabolism, etc. To imagine something without a membrane that functions like an organelle and coexist in the dense intracellular milieu is a very painstaking job. However, a close approximation one can guess is the liquid droplet. These condensates arise by liquid -liquid phase separation, simplest example is that of vapour during boiling water, oil in salad dressing or oil water mixture. These liquid like property renders these condensates their functional state where the molecules can rapidly diffuse in or out of these droplets. However, with time and certain physiological state these condensates can turn to gel or more solid like states. The protein aggregates we discussed earlier are also now considered to be arising from this process. The critical factor for forming these condensates are molecules that can interact with other molecules very efficiently. The proteins, RNA and DNA qualifies this criterion strongly and are reported to be the drivers of this condensate formation. The highlighting fact thus is the ability of the condensate forming proteins to become more insoluble and become aggregates. As has been previously discussed, protein undergoes aggregation during aging and the long-lived mutant have more protein aggregates. Moreover, researches now boil down to the fact that condensates can become aggregates provided the physiological milieu inside of it. We therefore take onto to understanding how the proteins that can form condensates behaves during aging and what are the regulators of these condensates. This aims at understanding condensates that can be targeted pharmacologically for aging healthy. We found that this condensate forming proteins are present in excess in normal and long lived mutant. However, these proteins do aggregate more in the long lived daf-2 mutant. Interestingly, the condensate forming proteins that contributes more for the aggregation, are the proteins that have their function during the embryonic developmental stages. One of the aging theories argues that the proteins might be functionally active at one stage of life and can be harmful at later stage of life. It is indeed reported that these condensates forming developmental proteins when stripped off during later life, the animals live longer. Thus, we comprehend that these proteins do form the functional condensates during the developmental stages of the animal and then it aggregates, to reduce the harmful effect that might arise if it remained functional. Thus, it suggests a protective aggregation response during aging. This strategy can not only keep the noxious protein out from the pool but can also store excess proteins that might be needed for later in life if needed. One such example is during aging the C. elegans hermaphrodites are exhausted of their sperms but they have their eggs intact that can be fertilized. Once fertilized, there will be downstream cell cycle activation and numerous proteins will be needed. Thus, these hermaphrodites might also be unknowingly has synthesized such cell cycle related proteins which are not used by then and which would take significant energy to degrade and resynthesize these proteins if at any point there are availability of sperms to fertilize and starts downstream cell cycle. Thus, sequestration of these proteins can also be protective as and when required they can be solubilized back and be available for function. If these proteins are forming condensates or aggregates, what are the essential regulators of these? In silico analysis from ours and in accordance with the previous reports, we observed small heat shock proteins (sHSPs) to be the central regulators of these condensates and acts as the Policemen here. These sHSPs can selectively aggregate these proteins thus facilitating the protective aggregation response. A corollary to this is what we discussed as the Policemen encircling the angry mob. We are at the very beginning of our understanding the beneficial condensates and their regulators; how does these condensates form and dissolve. How these affect aging? The target of which is to slowdown time for the aggregation, block its or dissolve it if necessary. The crux of this condensate biology has started to establish its mark in aging biology and we are on a mission to understand this where we desire to find out therapeutic strategy for neurodegeneration, and other aggregation related disorders and to reach our dream of healthy aging.
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