- Email: [email protected]
Targeting protein-protein interactions in heat shock protein 70 (Hsp70) to treat neurodegenerative disease
P512
Symposia: S3-02: Proteostasis
index has increased. Work is currently done to integrate dementia/AD research into the FINRISK study. The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study originates in the FINRISK study and has indicated several modifiable risk factors for Alzheimer’s disease (AD), and their interactions with genetic factors. CAIDE study has also enabled studying differences in risk factor profiles at midlife and late-life and risk factor dynamics over time in relation to cognitive changes. The possibilities that arise from combining large survey databases with structured and detailed health registers will be discussed. Scoring tools for estimating dementia risk in different age groups have been recently formulated. Such tools are important for selecting participants in clinical/ preventive trials, and for health education and community planning. Finland has long-term tradition in successful intervention studies to reduce the burden of CVD risk factors. The North Karelia project in the 1970’s and the Diabetes Prevention Study in 1990s have shown that lifestyle changes can be achieved and that these will translate in reduced morbidity. Experiences from two ongoing intervention studies with cognitive outcomes, the Dose Responses to Exercise Training and the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) will be presented. Conclusions: A lifelong perspective is needed for managing dementia. Lessons learned from CVD prevention can be integrated to dementia research on the way from knowledge to action. SYMPOSIA: S3-02 PROTEOSTASIS S3-02-01
PROTEOSTASIS: MONITORING THE HEALTH OF THE PROTEOME IN BIOLOGY, AGING AND DISEASE
Richard Morimoto, Northwestern University, Evanston, Illinois, United States. Contact e-mail: [email protected] Background: The stability of the proteome is essential for all aspects of cellular function, cellular health, organismal longevity. This is achieved by robust stress signaling pathways that recognize and respond to protein damage and proteostatic networks (PN) that ensure proper protein synthesis, folding, translocation, assembly, and clearance. Under optimal conditions the PN minimizes the stress of misfolded and aggregated proteins that arise from genetic polymorphisms, error-prone synthesis, mutations, stress, and aging. Fluctuations in the protein quality control are costly and can lead to the disruption of the proteostasis network resulting in collateral damage to metastable proteins and the amplification of non-native species. Thus, the enhanced risk during aging for age-associated diseases including, cancer, immunological disease, metabolic disease, and neurodegeneration. This is exemplified by the chronic expression of aggregation-prone proteins ie., polyglutamine-expansion proteins or mutant SOD1, that contributes to the global collapse of proteostasis by interference and competition for chaperones, thus affecting the folding and stability of other essential proteins that are intrinsically metastable, and interfering with chaperone-dependent cellular processes. Moreover, aging itself has widespread deleterious consequences on the heat shock response and the lumen unfolded protein response, that can be suppressed by genetic modifiers and small molecule proteostasis regulators to restore the proteome. The transmission of the environmental stress signal involves not only intracellular events but also cell non-autonomous signaling among tissues to integrate cell stress and proteostasis networks across tissues for optimal organismal health. S3-02-02
AUTOPHAGY AND NEURODEGENERATION
Ana Maria Cuervo, Albert Einstein College of Medicine, New York, United States. Contact e-mail: [email protected] Background: Alterations in cellular proteostasis are a common feature to many neurodegenerative disorders. Cells, including neurons, are well equipped with systems that protect them against protein toxicity and that include both chaperones and proteolytic systems. Autophagy is one of the proteolytic systems that by targeting altered or damaged proteins to lysosomes contributes to cellular quality control. Three different types of autophagy have been described in mammalian cells: macroautophagy, microautophagy
and chaperone-mediated autophagy (CMA). The better molecular characterization of the two stress-induced autophagic pathways, macroautophagy and CMA, have considerably advanced our understanding of the physiological role of these autophagic pathways. In addition, autophagy malfunctioning has been involved in the pathogenesis of detrimental human pathologies that manifest with aging such as cancer, neurodegenerative and metabolic diseases. In this talk, I will describe the two-sided relationship between pathogenic proteins and autophagy and that include the fact that autophagy contributes to the removal of pathogenic proteins, but in many instances pathogenic proteins can exert on the activity of different autophagic pathways. Regarding clearance of pathogenic proteins, I will discuss the contribution of macroautophagy to the selective removal of protein inclusions. I will also use different examples of aggregopathies to illustrate the contribution of alterations in macroautophagy and CMA to neuronal pathogenesis. Lastly, I will comment on the functional decline of autophagy with age and the efforts of my group to restore normal autophagic activity in old rodents, which allow us to evaluate the importance of maintaining proper protein removal until advanced ages. S3-02-03
TARGETING PROTEIN-PROTEIN INTERACTIONS IN HEAT SHOCK PROTEIN 70 (HSP70) TO TREAT NEURODEGENERATIVE DISEASE
Jason Gestwicki, University of California at San Francisco, San Francisco, California, United States. Contact e-mail: [email protected] Background: Heat shock protein 70 (Hsp70) is a molecular chaperone that plays critical roles in protein quality control and protein homeostasis (e.g., proteostasis). In these tasks, Hsp70 is assisted by co-chaperones, including J proteins and nucleotide exchange factors (NEFs), which bind Hsp70 and shape its activities. One task of Hsp70 and its co-chaperones is to identify the misfolded proteins that accumulate in neurodegenerative disease, such as tauopathies and polyglutamine (polyQ) expansion disorders, and the Hsp70 system appears to protect against these diseases in healthy individuals. Methods: To better understand Hsp70’s roles in this process, our strategy is to screen for drug-like small molecules that control the protein-protein interactions (PPIs) between Hsp70 and its critical cochaperones. Results: Using inhibitors of specific PPIs in the Hsp70 system, our key finding is that that inhibitors of the Hsp70-NEF interaction restore normal proteostasis in tauopathy and polyQ models by promoting the normal triage activity of the chaperone. These molecules reduce the accumulation of misfolded protein and restore normal functions in disease models. Conclusions: These results suggest new ways of restoring proteostasis by targeting PPIs in the Hsp70 pathway. S3-02-04
DEVELOPING USP14 INHIBITORS AS DISEASE-MODIFYING THERAPEUTICS FOR PROTEIN AGGREGATION DISEASES
Peter Reinhart1, Anjanabha Saha1, Andres Hurtado-Lorenzo1, Mohmmad Hafiz1, James Soper1, Eva Nokes1, Megan Foley1, Jyoti Malhotra1, Adriana Villella1, Eric Roskelley1, David Hurtado1, Ken Longo1, Ken Giuliano1, Dan Garza1, Brad Tait1, Markus Haeberlein1, Randy King2, Daniel Finley2, 1Proteostasis Therapeutics, Cambridge, Massachusetts, United States; 2Harvard Medical School, Boston, Massachusetts. Background: Protein aggregation disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are associated with the accumulation of misfolded proteins in the brain. Such protein aggregates can be cleared by a number of mechanisms including protein ubiquitination followed by proteasome-mediated degradation. The degradation of ubiquitinated proteins is limited by the activity of proteasome-associated deubiquitinating enzymes, such as Usp14, that trim the associated ubiquitin chains prior to substrate degradation. We have developed a drug discovery platform to evaluate whether selective inhibition of Usp14 by small molecules can lower the accumulation of aggregated proteins, such as a -synuclein in PD, tau in AD, or TDP-43 for ALS, by enhancing the degradation of misfolded proteins. Methods: We have used HTS screening to identify and develop Usp14 inhibitors to enhance the clearance of disease-relevant proteins prone to
Symposia: S3-02: Proteostasis
index has increased. Work is currently done to integrate dementia/AD research into the FINRISK study. The Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study originates in the FINRISK study and has indicated several modifiable risk factors for Alzheimer’s disease (AD), and their interactions with genetic factors. CAIDE study has also enabled studying differences in risk factor profiles at midlife and late-life and risk factor dynamics over time in relation to cognitive changes. The possibilities that arise from combining large survey databases with structured and detailed health registers will be discussed. Scoring tools for estimating dementia risk in different age groups have been recently formulated. Such tools are important for selecting participants in clinical/ preventive trials, and for health education and community planning. Finland has long-term tradition in successful intervention studies to reduce the burden of CVD risk factors. The North Karelia project in the 1970’s and the Diabetes Prevention Study in 1990s have shown that lifestyle changes can be achieved and that these will translate in reduced morbidity. Experiences from two ongoing intervention studies with cognitive outcomes, the Dose Responses to Exercise Training and the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) will be presented. Conclusions: A lifelong perspective is needed for managing dementia. Lessons learned from CVD prevention can be integrated to dementia research on the way from knowledge to action. SYMPOSIA: S3-02 PROTEOSTASIS S3-02-01
PROTEOSTASIS: MONITORING THE HEALTH OF THE PROTEOME IN BIOLOGY, AGING AND DISEASE
Richard Morimoto, Northwestern University, Evanston, Illinois, United States. Contact e-mail: [email protected] Background: The stability of the proteome is essential for all aspects of cellular function, cellular health, organismal longevity. This is achieved by robust stress signaling pathways that recognize and respond to protein damage and proteostatic networks (PN) that ensure proper protein synthesis, folding, translocation, assembly, and clearance. Under optimal conditions the PN minimizes the stress of misfolded and aggregated proteins that arise from genetic polymorphisms, error-prone synthesis, mutations, stress, and aging. Fluctuations in the protein quality control are costly and can lead to the disruption of the proteostasis network resulting in collateral damage to metastable proteins and the amplification of non-native species. Thus, the enhanced risk during aging for age-associated diseases including, cancer, immunological disease, metabolic disease, and neurodegeneration. This is exemplified by the chronic expression of aggregation-prone proteins ie., polyglutamine-expansion proteins or mutant SOD1, that contributes to the global collapse of proteostasis by interference and competition for chaperones, thus affecting the folding and stability of other essential proteins that are intrinsically metastable, and interfering with chaperone-dependent cellular processes. Moreover, aging itself has widespread deleterious consequences on the heat shock response and the lumen unfolded protein response, that can be suppressed by genetic modifiers and small molecule proteostasis regulators to restore the proteome. The transmission of the environmental stress signal involves not only intracellular events but also cell non-autonomous signaling among tissues to integrate cell stress and proteostasis networks across tissues for optimal organismal health. S3-02-02
AUTOPHAGY AND NEURODEGENERATION
Ana Maria Cuervo, Albert Einstein College of Medicine, New York, United States. Contact e-mail: [email protected] Background: Alterations in cellular proteostasis are a common feature to many neurodegenerative disorders. Cells, including neurons, are well equipped with systems that protect them against protein toxicity and that include both chaperones and proteolytic systems. Autophagy is one of the proteolytic systems that by targeting altered or damaged proteins to lysosomes contributes to cellular quality control. Three different types of autophagy have been described in mammalian cells: macroautophagy, microautophagy
and chaperone-mediated autophagy (CMA). The better molecular characterization of the two stress-induced autophagic pathways, macroautophagy and CMA, have considerably advanced our understanding of the physiological role of these autophagic pathways. In addition, autophagy malfunctioning has been involved in the pathogenesis of detrimental human pathologies that manifest with aging such as cancer, neurodegenerative and metabolic diseases. In this talk, I will describe the two-sided relationship between pathogenic proteins and autophagy and that include the fact that autophagy contributes to the removal of pathogenic proteins, but in many instances pathogenic proteins can exert on the activity of different autophagic pathways. Regarding clearance of pathogenic proteins, I will discuss the contribution of macroautophagy to the selective removal of protein inclusions. I will also use different examples of aggregopathies to illustrate the contribution of alterations in macroautophagy and CMA to neuronal pathogenesis. Lastly, I will comment on the functional decline of autophagy with age and the efforts of my group to restore normal autophagic activity in old rodents, which allow us to evaluate the importance of maintaining proper protein removal until advanced ages. S3-02-03
TARGETING PROTEIN-PROTEIN INTERACTIONS IN HEAT SHOCK PROTEIN 70 (HSP70) TO TREAT NEURODEGENERATIVE DISEASE
Jason Gestwicki, University of California at San Francisco, San Francisco, California, United States. Contact e-mail: [email protected] Background: Heat shock protein 70 (Hsp70) is a molecular chaperone that plays critical roles in protein quality control and protein homeostasis (e.g., proteostasis). In these tasks, Hsp70 is assisted by co-chaperones, including J proteins and nucleotide exchange factors (NEFs), which bind Hsp70 and shape its activities. One task of Hsp70 and its co-chaperones is to identify the misfolded proteins that accumulate in neurodegenerative disease, such as tauopathies and polyglutamine (polyQ) expansion disorders, and the Hsp70 system appears to protect against these diseases in healthy individuals. Methods: To better understand Hsp70’s roles in this process, our strategy is to screen for drug-like small molecules that control the protein-protein interactions (PPIs) between Hsp70 and its critical cochaperones. Results: Using inhibitors of specific PPIs in the Hsp70 system, our key finding is that that inhibitors of the Hsp70-NEF interaction restore normal proteostasis in tauopathy and polyQ models by promoting the normal triage activity of the chaperone. These molecules reduce the accumulation of misfolded protein and restore normal functions in disease models. Conclusions: These results suggest new ways of restoring proteostasis by targeting PPIs in the Hsp70 pathway. S3-02-04
DEVELOPING USP14 INHIBITORS AS DISEASE-MODIFYING THERAPEUTICS FOR PROTEIN AGGREGATION DISEASES
Peter Reinhart1, Anjanabha Saha1, Andres Hurtado-Lorenzo1, Mohmmad Hafiz1, James Soper1, Eva Nokes1, Megan Foley1, Jyoti Malhotra1, Adriana Villella1, Eric Roskelley1, David Hurtado1, Ken Longo1, Ken Giuliano1, Dan Garza1, Brad Tait1, Markus Haeberlein1, Randy King2, Daniel Finley2, 1Proteostasis Therapeutics, Cambridge, Massachusetts, United States; 2Harvard Medical School, Boston, Massachusetts. Background: Protein aggregation disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD) are associated with the accumulation of misfolded proteins in the brain. Such protein aggregates can be cleared by a number of mechanisms including protein ubiquitination followed by proteasome-mediated degradation. The degradation of ubiquitinated proteins is limited by the activity of proteasome-associated deubiquitinating enzymes, such as Usp14, that trim the associated ubiquitin chains prior to substrate degradation. We have developed a drug discovery platform to evaluate whether selective inhibition of Usp14 by small molecules can lower the accumulation of aggregated proteins, such as a -synuclein in PD, tau in AD, or TDP-43 for ALS, by enhancing the degradation of misfolded proteins. Methods: We have used HTS screening to identify and develop Usp14 inhibitors to enhance the clearance of disease-relevant proteins prone to