The increase of molecular chaperones and prevention of protein misfolding in treating neurodegeneration
Sarah Temple
Introduction
There is an urgent need for productive therapeutic strategies that could halt or reverse neuronal cell death and deterioration in neurodegenerative disorders. Scientists’ focus on treatment has previously addressed disease symptoms, attempting to increase macro- and micronutrients in diet because these nutrients reduce the numerous genetic, environmental, and endogenous mechanisms that begin the process of neurodegeneration. These mechanisms include “defective protein degradation and aggregation, many related to the ubiquitin-proteasomal system, oxidative stress and free radical formation, impaired bioenergetics and mitochondrial dysfunctions, and ‘neuroinflammatory' processes”1(101). Modification of lifestyle factors like diet is aimed at increasing specific micronutrients directly related to the health of neuronal cells2. Focus on treating with appropriate nutrients has been attractive to researchers because it is based on the information that these diseases progress with age and the effects that macro- and micronutrients have on neuronal health, information already well understood by researchers. Because many other components impact neurodegeneration, this treatment is not fully effective2.
Scientists have previously focused on attempting to treat neurodegeneration with the consumption of nutrients necessary to maintain brain health. Since increase of micronutrients (group B vitamins related to homo-cysteine metabolism, anti-oxidant vitamins C and E, flavonoids, polyunsatured omega-3 fatty acids, vitamin D) and macronutrients (fish) is simply a lifestyle change, it would be extremely easy to treat neurodegeneration using these nutrients because they can prevent cognitive decline and dementia1. Experts are aware that oxidative stress is a common cause of neurodegeneration, causing dementia and cognitive decline in patients. Oxidative stress participates in very early stages of diseases such as Alzheimer’s and also plays a significant role in triggering lesion and toxic substance formation creating neuron and glial cell death. Antioxidant vitamins C and E protect against oxidation, and these vitamins decrease toxicity of the beta-amyloid protein and reduce cell damage2. Caloric restriction may also have significant benefits on brain aging and health; Some studies show that “higher adiposity at mid-life is associated with a higher risk for dementia or AD in epidemiologic studies”3(1360). But intake of specific nutrients has been much more accepted as a possible way of treatment because other studies have shown that there is no correlation between caloric restriction and brain health, making it difficult to use this information towards a successful prevention method for neurodegeneration.
Although antioxidant vitamins protect against oxidation, studies related to the consumption of foods with antioxidants have produced inconsistent results, some showing an increase of cognitive function in patients and others showing that the intake of antioxidants had no impact on the patient at all3. Other micronutrient intake such as group B vitamins related to homo-cysteine metabolism, flavonoids, polyunsaturated omega-3 fatty acids, and vitamin D has proven to have the same inconsistent results as studies focusing on antioxidants. Since both antioxidant and group B vitamin intake have not been proven fully effective in symptom decline, it is impossible to accept the uptake of micro and macro nutrients as an effective treatment method for neurodegeneration.
Treating neurodegeneration with the intake of nutrients has also been proven ineffective because of the many factors related to the beginning of the cycle of neuronal and glial cell death. Nutrient intake attempts to attack neurodegenerative diseases from the beginning; the endogenous, genetic and environmental factors that begin the process of neurodegeneration. Since these factors are so numerous and attack the neuronal system as the organism ages, it is impossible to prevent neurodegeneration from this stance4. It is also impossible to be sure which specific factor(s) are starting this degenerative process in each patient, so scientists must target secondary causes for possible treatment.
Targeting secondary causes and processes present in most neurodegenerative diseases has shown potential in future treatment. These causes involve similar systemic and cellular properties that suggest common deterioration processes. In many neurodegenerative diseases, protein misfolding begins the cycle of cell deterioration and death. Because protein misfolding is the common factor related to most neurodegenerative diseases, it would be most effective to target treatment from this angle, even though it is less understood. Protein folding is the process which converts newly synthesized proteins into functional molecules. In patients with neurodegenerative disease, this process becomes disrupted, causing protein misfolding and the subsequent aggregation, which increases as one becomes older. High numbers of misfolded and aggregated proteins produce toxic activity, triggering vicious cycles leading to dysfunction and death of neuronal and glial cells4. Toxic activity and disfunction damage cell networks are damaged over time, creating symptoms like dementia, one of the main symptoms of most neurodegenerative diseases. The brain utilizes molecular chaperones, which recognize and refold misfolded proteins, as well as intracellular proteases to prevent protein misfolding, but these defense mechanisms are compromised by the age-related factors that trigger neurodegenerative diseases4. There is still much to be researched about the process and causes of neuronal degeneration and death, but if protein misfolding can be prevented by strengthening molecular chaperones, we may be able to deter or prevent these neurodegenerative diseases.
Process of protein misfolding and protein aggregation
By treating protein misfolding, the secondary cause of neurodegeneration, scientists can prevent cell deterioration and death most effectively. Protein misfolding occurs in every human body, but when numerous proteins misfold and form aggregates, the cycle of cell death begins. Protein folding is a normal process that “converts newly synthesized proteins to physiologically functional molecules”4(460). In patients with neurodegenerative diseases, genetic mutations or environmental factors can instigate protein misfolding and aggregation of specific types of proteins that cause disease. Since similar factors can instigate protein misfolding, “similar pathological mechanisms may underlie the pathogenesis of the different neurodegenerative disorders”5(1). Although we still do not fully understand which exact underlying mechanisms of protein misfolding cause each specific neurodegenerative disease, researchers are beginning to focus on the prevention of protein misfolding and abnormal aggregation as the common factor that could prevent neurodegeneration.
“The long term health of the cell is inextricably linked to protein quality control”5(1427). Researchers have discovered that about 30% of newly synthesized proteins are incorrectly folded and degraded in a healthy organism6. The protein quality control system used to handle misfolded proteins and maintain protein homeostasis is normally able to control all of these misfolded proteins. However, in a situation where the number of misfolded and aggregated proteins increases significantly, it becomes difficult for molecular chaperones to refold all of them. Further, as the capacity of the protein quality control system declines with aging, cells lose their ability to efficiently deal with misfolded proteins5. Deterioration of the protein quality control system over time furthers accumulation of dead neuronal cells caused by misfolding.
The misfolding and aggregation of specific proteins results from genetic mutations causing neurodegeneration. Although the proteins causing each disease are structurally unrelated, the process of misfolding remains the same for all proteins, making it possible to target all neurodegenerative diseases resulting from any type of misfolded protein. Although these proteins are structurally and functionally unrelated, most tend to adopt a highly stable β-sheet structure that causes aggregation and toxic activity. After the β-sheet structures form, misfolded proteins form “intermediate-sized soluble oligomers, which are thought to promote oxidative stress, disrupt calcium homeostasis, titrate chaperone proteins away from other essential cellular functions and engage in other processes that are disruptive to cellular health”7(930), leading to extreme toxic activity, cell death, and neurodegenerative disease. Scientists are looking for chaperone genes that create healthy proteins and decrease abnormal protein aggregation in the entire proteome in an attempt to deter or prevent all types of proteopathies.
Molecular chaperones and the “heat-shock” process of cell protection
Molecular chaperones are crucial to the functionality and protection of proteins to ensure the long term health of the cell. The system is controlled by molecular chaperones that balance and protect protein homeostasis. These chaperones involved in the cellular protein quality control systems “recognize misfolded proteins, assist in their refolding, prevent their aggregation, and help to repair the damaged proteins”8(324). Lack of chaperones or their inability to fully protect homeostasis can severely damage the neuronal system. Experts are aware that organisms have an abundance of molecular chaperones to restore the folding equilibrium of proteins. Numerous chaperones should be able to provide the system with the ability to adapt to proteotoxic stress, but there are still not enough chaperones produced to handle a situation of excessive stress (e.g. neurodegenerative disease).
The system should be able to produce more chaperones to refold increasing numbers of misfolded proteins in an excessive-stress situation. But experts are currently unable to explain why the protein quality control system does not react to excessive stress. By researching cells’ most effective stress response process, the heat-shock process of cell protection, scientists are understanding more about what triggers the production of more molecular chaperones and what can be done to trigger and increase chaperones in the case of neurodegenerative disease. In a situation of increased stress (heat, cold, or lack of oxygen), some molecular chaperones are activated to better protect cells. The heat shock response triggers the over-expression of genes that function to protect against proteotoxic stress in every cell. The increase of genes then induces a regulatory domino-effect that recovers and adapts the cell 9(11). The heat shock response exemplifies the ability for these type of chaperones to detect stress and react appropriately to it. But experts have observed that in many situations this response is incompletely activated, for example in an instance of whole-body stress. These observations bring up the question of whether chaperones affected by the heat-shock process can be activated by a pharmacological induction of heat or cold, or oxygen deprivation to increase molecular chaperones needed in a situation where a high level of protein misfolding takes place10.
Recent studies in cell culture, fruitfly, worm, and mouse models of protein misfolding-based neurodegenerative diseases have focused on pharmacologically enhancing the protein-folding capacity of cells via elevated expression of chaperone proteins. These studies have shown therapeutic potential in relation to treating neurodegenerative disease in humans. Advances have been made in chemically activating the heat shock response, proven to be currently the most promising method of activating molecular chaperones to treat neurodegenerative diseases7. Heat shock transcription factors (HSFs) mediate the inducible transcriptional response of genes that encode heat shock proteins. There are various types of chaperone proteins in the human protein quality control system, including αB‐crystallin, heat shock protein 27 (HSP27), HSP40, HSP70 and HSP90, along with class I and class II chaperonins. HSP27 is the only chaperone protein that is naturally elevated by the human heat shock factor HSF1 but it has been discovered that all chaperones function individually and as part of larger heterocomplexes to prevent protein misfolding and protein aggregation7. Since these chaperones function as a whole, activation of the heat-shock response HSF1 in the heat shock protein HSP27 could be productive in increasing overall cell protection.
Future research and conclusion
Millions of people suffer from neurodegenerative disease and there is currently no cure or effective way of prevention. The further study of protein misfolding, protein aggregation, and molecular chaperones is crucial in the process of understanding and preventing the cycle of neuronal dysfunction and death. Strengthening molecular chaperones to better defend the protein quality control system could be the most effective way to treat or cure neurodegeneration.
Experts have discovered that, in diseases caused by misfolding, chaperones are either insufficiently triggered by the increase of misfolded proteins so cannot fully protect against aggregation, toxic activity, and cell death. It is possible that the cell has little extra chaperone capacity, implying that the folding process is delicate with little room for error3. We are still trying to find out if this is in fact true and what can be done to help trigger the stress-response of the chaperones to protect more efficiently against an increased production of misfolded proteins. Research must be continued regarding chaperone function and mechanics to address and attempt to solve the aggregation of misfolded proteins, the key to treating patients affected by neurodegenerative disease.
There is a huge global research field dedicated to identifying possible therapies and treatments for neurodegenerative diseases. Experts are currently exploring the process of heat-shock as a possible way of treatment if it can be possible to trigger the increase of chaperones this way. Although many molecules that activate the heat-shock factor HSF1 have been identified, the majority are activated only by causing cellular stress, which has too much negative impact on cell health. To prevent such stress,scientists are searching for a direct pharmacological activator of HSF1. The discovery of this activator molecule(s) will be groundbreaking in the neurodegeneration research field. Scientists believe that the ideal activator of HSF1 would be a small molecule that could directly bind to HSF1 and promote its transition from a monomer to a homotrimer. As the ideal HSF1 activator would not cause proteotoxic stress, such a molecule would “stimulate modest but chronic expression of chaperone proteins, resulting in the amelioration of neurodegenerative disease phenotypes”7(940). But, if this activator is discovered, bringing it to clinical trial would be a lengthy process. Researching and understanding more about how the process of misfolding and protein defense mechanisms works, along with searching for a functional activator of the protein HSF1 without causing toxic activity, is crucial in advancing the process of finding a cure for neurodegenerative disease.
References
1. Jellinger K. General aspects of neurodegeneration. Journal Of Neural Transmission-Supplement [serial online]. 2003;(65):101-144. Available from: Science Citation Index, Ipswich, MA. Accessed November 16, 2014.
2. Gillette-Guyonnet S, Secher M, Vellas B. Nutrition and neurodegeneration: epidemiological evidence and challenges for future research. British J Of Clinical Pharmacology [serial online]. March 2013;75(3):738-755. Available from: Academic Search Alumni Edition, Accessed November 1, 2014.
3. Whitmer RA, Gunderson EP, Barrett-Connor E, Quesenberry CP Jr, Yaffe K. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ [serial online]. 2005, 330:1360-1364. Available from: PubMed, Accessed November 3, 2014
4. Jellinger K. Basic mechanisms of neurodegeneration: A critical update. J Of Cellular And Molecular Medicine [serial online]. March 2010;14(3):457-487. Available from: Scopus®, Accessed October 12, 2014.
5. Takalo M, Salminen A, Soininen H, Hiltunen M, Haapasalo A. Protein aggregation and degradation mechanisms in neurodegenerative diseases. American Journal Of Neurodegenerative Disease [serial online]. March 2013;2(1):1-14. Available from: Academic Search Complete, Ipswich, MA. Accessed November 16, 2014.
6. Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 2000; 404: 770-774.
7. Neef D, Jaeger A, Thiele D. Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nature Reviews Drug Discovery [serial online]. December 2011;10(12):930-944. Available from: Academic Search Alumni Edition, Ipswich, MA. Accessed November 16, 2014.
8. Hartl FU, Bracher A, Hayer-Hartl M. Molecular chaperones in protein folding and proteostasis. Nature 2011; 475: 324-332.
9. Morimoto R. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes & Development. 1998;12(24):3788-3796. Available from: MEDLINE, Accessed October 21, 2014.
10. Morimoto R. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes & Development [serial online]. 2010;22(11):1427-1438. Available from: Science Citation Index, Accessed October 23, 2014.
There is an urgent need for productive therapeutic strategies that could halt or reverse neuronal cell death and deterioration in neurodegenerative disorders. Scientists’ focus on treatment has previously addressed disease symptoms, attempting to increase macro- and micronutrients in diet because these nutrients reduce the numerous genetic, environmental, and endogenous mechanisms that begin the process of neurodegeneration. These mechanisms include “defective protein degradation and aggregation, many related to the ubiquitin-proteasomal system, oxidative stress and free radical formation, impaired bioenergetics and mitochondrial dysfunctions, and ‘neuroinflammatory' processes”1(101). Modification of lifestyle factors like diet is aimed at increasing specific micronutrients directly related to the health of neuronal cells2. Focus on treating with appropriate nutrients has been attractive to researchers because it is based on the information that these diseases progress with age and the effects that macro- and micronutrients have on neuronal health, information already well understood by researchers. Because many other components impact neurodegeneration, this treatment is not fully effective2.
Scientists have previously focused on attempting to treat neurodegeneration with the consumption of nutrients necessary to maintain brain health. Since increase of micronutrients (group B vitamins related to homo-cysteine metabolism, anti-oxidant vitamins C and E, flavonoids, polyunsatured omega-3 fatty acids, vitamin D) and macronutrients (fish) is simply a lifestyle change, it would be extremely easy to treat neurodegeneration using these nutrients because they can prevent cognitive decline and dementia1. Experts are aware that oxidative stress is a common cause of neurodegeneration, causing dementia and cognitive decline in patients. Oxidative stress participates in very early stages of diseases such as Alzheimer’s and also plays a significant role in triggering lesion and toxic substance formation creating neuron and glial cell death. Antioxidant vitamins C and E protect against oxidation, and these vitamins decrease toxicity of the beta-amyloid protein and reduce cell damage2. Caloric restriction may also have significant benefits on brain aging and health; Some studies show that “higher adiposity at mid-life is associated with a higher risk for dementia or AD in epidemiologic studies”3(1360). But intake of specific nutrients has been much more accepted as a possible way of treatment because other studies have shown that there is no correlation between caloric restriction and brain health, making it difficult to use this information towards a successful prevention method for neurodegeneration.
Although antioxidant vitamins protect against oxidation, studies related to the consumption of foods with antioxidants have produced inconsistent results, some showing an increase of cognitive function in patients and others showing that the intake of antioxidants had no impact on the patient at all3. Other micronutrient intake such as group B vitamins related to homo-cysteine metabolism, flavonoids, polyunsaturated omega-3 fatty acids, and vitamin D has proven to have the same inconsistent results as studies focusing on antioxidants. Since both antioxidant and group B vitamin intake have not been proven fully effective in symptom decline, it is impossible to accept the uptake of micro and macro nutrients as an effective treatment method for neurodegeneration.
Treating neurodegeneration with the intake of nutrients has also been proven ineffective because of the many factors related to the beginning of the cycle of neuronal and glial cell death. Nutrient intake attempts to attack neurodegenerative diseases from the beginning; the endogenous, genetic and environmental factors that begin the process of neurodegeneration. Since these factors are so numerous and attack the neuronal system as the organism ages, it is impossible to prevent neurodegeneration from this stance4. It is also impossible to be sure which specific factor(s) are starting this degenerative process in each patient, so scientists must target secondary causes for possible treatment.
Targeting secondary causes and processes present in most neurodegenerative diseases has shown potential in future treatment. These causes involve similar systemic and cellular properties that suggest common deterioration processes. In many neurodegenerative diseases, protein misfolding begins the cycle of cell deterioration and death. Because protein misfolding is the common factor related to most neurodegenerative diseases, it would be most effective to target treatment from this angle, even though it is less understood. Protein folding is the process which converts newly synthesized proteins into functional molecules. In patients with neurodegenerative disease, this process becomes disrupted, causing protein misfolding and the subsequent aggregation, which increases as one becomes older. High numbers of misfolded and aggregated proteins produce toxic activity, triggering vicious cycles leading to dysfunction and death of neuronal and glial cells4. Toxic activity and disfunction damage cell networks are damaged over time, creating symptoms like dementia, one of the main symptoms of most neurodegenerative diseases. The brain utilizes molecular chaperones, which recognize and refold misfolded proteins, as well as intracellular proteases to prevent protein misfolding, but these defense mechanisms are compromised by the age-related factors that trigger neurodegenerative diseases4. There is still much to be researched about the process and causes of neuronal degeneration and death, but if protein misfolding can be prevented by strengthening molecular chaperones, we may be able to deter or prevent these neurodegenerative diseases.
Process of protein misfolding and protein aggregation
By treating protein misfolding, the secondary cause of neurodegeneration, scientists can prevent cell deterioration and death most effectively. Protein misfolding occurs in every human body, but when numerous proteins misfold and form aggregates, the cycle of cell death begins. Protein folding is a normal process that “converts newly synthesized proteins to physiologically functional molecules”4(460). In patients with neurodegenerative diseases, genetic mutations or environmental factors can instigate protein misfolding and aggregation of specific types of proteins that cause disease. Since similar factors can instigate protein misfolding, “similar pathological mechanisms may underlie the pathogenesis of the different neurodegenerative disorders”5(1). Although we still do not fully understand which exact underlying mechanisms of protein misfolding cause each specific neurodegenerative disease, researchers are beginning to focus on the prevention of protein misfolding and abnormal aggregation as the common factor that could prevent neurodegeneration.
“The long term health of the cell is inextricably linked to protein quality control”5(1427). Researchers have discovered that about 30% of newly synthesized proteins are incorrectly folded and degraded in a healthy organism6. The protein quality control system used to handle misfolded proteins and maintain protein homeostasis is normally able to control all of these misfolded proteins. However, in a situation where the number of misfolded and aggregated proteins increases significantly, it becomes difficult for molecular chaperones to refold all of them. Further, as the capacity of the protein quality control system declines with aging, cells lose their ability to efficiently deal with misfolded proteins5. Deterioration of the protein quality control system over time furthers accumulation of dead neuronal cells caused by misfolding.
The misfolding and aggregation of specific proteins results from genetic mutations causing neurodegeneration. Although the proteins causing each disease are structurally unrelated, the process of misfolding remains the same for all proteins, making it possible to target all neurodegenerative diseases resulting from any type of misfolded protein. Although these proteins are structurally and functionally unrelated, most tend to adopt a highly stable β-sheet structure that causes aggregation and toxic activity. After the β-sheet structures form, misfolded proteins form “intermediate-sized soluble oligomers, which are thought to promote oxidative stress, disrupt calcium homeostasis, titrate chaperone proteins away from other essential cellular functions and engage in other processes that are disruptive to cellular health”7(930), leading to extreme toxic activity, cell death, and neurodegenerative disease. Scientists are looking for chaperone genes that create healthy proteins and decrease abnormal protein aggregation in the entire proteome in an attempt to deter or prevent all types of proteopathies.
Molecular chaperones and the “heat-shock” process of cell protection
Molecular chaperones are crucial to the functionality and protection of proteins to ensure the long term health of the cell. The system is controlled by molecular chaperones that balance and protect protein homeostasis. These chaperones involved in the cellular protein quality control systems “recognize misfolded proteins, assist in their refolding, prevent their aggregation, and help to repair the damaged proteins”8(324). Lack of chaperones or their inability to fully protect homeostasis can severely damage the neuronal system. Experts are aware that organisms have an abundance of molecular chaperones to restore the folding equilibrium of proteins. Numerous chaperones should be able to provide the system with the ability to adapt to proteotoxic stress, but there are still not enough chaperones produced to handle a situation of excessive stress (e.g. neurodegenerative disease).
The system should be able to produce more chaperones to refold increasing numbers of misfolded proteins in an excessive-stress situation. But experts are currently unable to explain why the protein quality control system does not react to excessive stress. By researching cells’ most effective stress response process, the heat-shock process of cell protection, scientists are understanding more about what triggers the production of more molecular chaperones and what can be done to trigger and increase chaperones in the case of neurodegenerative disease. In a situation of increased stress (heat, cold, or lack of oxygen), some molecular chaperones are activated to better protect cells. The heat shock response triggers the over-expression of genes that function to protect against proteotoxic stress in every cell. The increase of genes then induces a regulatory domino-effect that recovers and adapts the cell 9(11). The heat shock response exemplifies the ability for these type of chaperones to detect stress and react appropriately to it. But experts have observed that in many situations this response is incompletely activated, for example in an instance of whole-body stress. These observations bring up the question of whether chaperones affected by the heat-shock process can be activated by a pharmacological induction of heat or cold, or oxygen deprivation to increase molecular chaperones needed in a situation where a high level of protein misfolding takes place10.
Recent studies in cell culture, fruitfly, worm, and mouse models of protein misfolding-based neurodegenerative diseases have focused on pharmacologically enhancing the protein-folding capacity of cells via elevated expression of chaperone proteins. These studies have shown therapeutic potential in relation to treating neurodegenerative disease in humans. Advances have been made in chemically activating the heat shock response, proven to be currently the most promising method of activating molecular chaperones to treat neurodegenerative diseases7. Heat shock transcription factors (HSFs) mediate the inducible transcriptional response of genes that encode heat shock proteins. There are various types of chaperone proteins in the human protein quality control system, including αB‐crystallin, heat shock protein 27 (HSP27), HSP40, HSP70 and HSP90, along with class I and class II chaperonins. HSP27 is the only chaperone protein that is naturally elevated by the human heat shock factor HSF1 but it has been discovered that all chaperones function individually and as part of larger heterocomplexes to prevent protein misfolding and protein aggregation7. Since these chaperones function as a whole, activation of the heat-shock response HSF1 in the heat shock protein HSP27 could be productive in increasing overall cell protection.
Future research and conclusion
Millions of people suffer from neurodegenerative disease and there is currently no cure or effective way of prevention. The further study of protein misfolding, protein aggregation, and molecular chaperones is crucial in the process of understanding and preventing the cycle of neuronal dysfunction and death. Strengthening molecular chaperones to better defend the protein quality control system could be the most effective way to treat or cure neurodegeneration.
Experts have discovered that, in diseases caused by misfolding, chaperones are either insufficiently triggered by the increase of misfolded proteins so cannot fully protect against aggregation, toxic activity, and cell death. It is possible that the cell has little extra chaperone capacity, implying that the folding process is delicate with little room for error3. We are still trying to find out if this is in fact true and what can be done to help trigger the stress-response of the chaperones to protect more efficiently against an increased production of misfolded proteins. Research must be continued regarding chaperone function and mechanics to address and attempt to solve the aggregation of misfolded proteins, the key to treating patients affected by neurodegenerative disease.
There is a huge global research field dedicated to identifying possible therapies and treatments for neurodegenerative diseases. Experts are currently exploring the process of heat-shock as a possible way of treatment if it can be possible to trigger the increase of chaperones this way. Although many molecules that activate the heat-shock factor HSF1 have been identified, the majority are activated only by causing cellular stress, which has too much negative impact on cell health. To prevent such stress,scientists are searching for a direct pharmacological activator of HSF1. The discovery of this activator molecule(s) will be groundbreaking in the neurodegeneration research field. Scientists believe that the ideal activator of HSF1 would be a small molecule that could directly bind to HSF1 and promote its transition from a monomer to a homotrimer. As the ideal HSF1 activator would not cause proteotoxic stress, such a molecule would “stimulate modest but chronic expression of chaperone proteins, resulting in the amelioration of neurodegenerative disease phenotypes”7(940). But, if this activator is discovered, bringing it to clinical trial would be a lengthy process. Researching and understanding more about how the process of misfolding and protein defense mechanisms works, along with searching for a functional activator of the protein HSF1 without causing toxic activity, is crucial in advancing the process of finding a cure for neurodegenerative disease.
References
1. Jellinger K. General aspects of neurodegeneration. Journal Of Neural Transmission-Supplement [serial online]. 2003;(65):101-144. Available from: Science Citation Index, Ipswich, MA. Accessed November 16, 2014.
2. Gillette-Guyonnet S, Secher M, Vellas B. Nutrition and neurodegeneration: epidemiological evidence and challenges for future research. British J Of Clinical Pharmacology [serial online]. March 2013;75(3):738-755. Available from: Academic Search Alumni Edition, Accessed November 1, 2014.
3. Whitmer RA, Gunderson EP, Barrett-Connor E, Quesenberry CP Jr, Yaffe K. Obesity in middle age and future risk of dementia: a 27 year longitudinal population based study. BMJ [serial online]. 2005, 330:1360-1364. Available from: PubMed, Accessed November 3, 2014
4. Jellinger K. Basic mechanisms of neurodegeneration: A critical update. J Of Cellular And Molecular Medicine [serial online]. March 2010;14(3):457-487. Available from: Scopus®, Accessed October 12, 2014.
5. Takalo M, Salminen A, Soininen H, Hiltunen M, Haapasalo A. Protein aggregation and degradation mechanisms in neurodegenerative diseases. American Journal Of Neurodegenerative Disease [serial online]. March 2013;2(1):1-14. Available from: Academic Search Complete, Ipswich, MA. Accessed November 16, 2014.
6. Schubert U, Anton LC, Gibbs J, Norbury CC, Yewdell JW, Bennink JR. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 2000; 404: 770-774.
7. Neef D, Jaeger A, Thiele D. Heat shock transcription factor 1 as a therapeutic target in neurodegenerative diseases. Nature Reviews Drug Discovery [serial online]. December 2011;10(12):930-944. Available from: Academic Search Alumni Edition, Ipswich, MA. Accessed November 16, 2014.
8. Hartl FU, Bracher A, Hayer-Hartl M. Molecular chaperones in protein folding and proteostasis. Nature 2011; 475: 324-332.
9. Morimoto R. Regulation of the heat shock transcriptional response: cross talk between a family of heat shock factors, molecular chaperones, and negative regulators. Genes & Development. 1998;12(24):3788-3796. Available from: MEDLINE, Accessed October 21, 2014.
10. Morimoto R. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes & Development [serial online]. 2010;22(11):1427-1438. Available from: Science Citation Index, Accessed October 23, 2014.