Molecular Mechanisms linking Aging, Abeta Proteotoxicity and Neurodegeneration

Summary

Principal Investigator: Jeffery W Kelly
Abstract: Aging increases the risk of neurodegeneration. Strong evidence implicates aggregation-mediated proteotoxicity as the cause of neurodegeneration in numerous clinically important diseases, including Alzheimer's disease, although the etiology is unclear. Emerging genetic data suggest that the aging process is linked by signaling pathways to the fidelity of protein homeostasis, including the ability to recover or dispose of misfolded or aggregated proteins. Overall this program project strives to meet two goals: 1) to understand the organismal, cell biological and molecular bases for the pathways that protect organisms from protein aggregation, and 2) to determine how these pathways become compromised as an organism ages. The Kelly Laboratory will focus on the biochemical characterization of the pathway(s) and the underlying molecular determinants of the disaggregase activity that appears to protect against age onset proteotoxicity in C. elegans and murine models of Alzheimer's and in human cells and they will test the hypothesis that amyloidogenesis is a constitutive process. The Balch Laboratory will generate senescence cell models to probe the role of age-dependent changes in exocytic and endocytic APR and Abeta processing that appear to contribute to proteotoxicity and will employ their expertise to perturb the exocytic and endocytic pathways to understand the genesis of Abeta proteotoxicity. The Dillin Laboratory will utilize genetic, proteomic and bioinformatics approaches and animal models of Alzheimer's disease to understand how and which aging-associated signaling pathways and downstream determinants affect proteotoxicity and they will carry out Abeta aggregate structure toxicity assessments in the worm Alzheimer's model. The bioinformatics, proteomics and neurosciences and neuropathology cores are each intimately associated with two or more of these projects that are themselves highly interdependent. The results obtained from this project will not only provide insight into the relationship between aging and neurodegeneration, but should provide the information necessary to develop therapeutic strategies for age-associated neurodegenerative diseases.
Funding Period: 2009-02-01 - 2014-04-30
more information: NIH RePORT

Top Publications

  1. pmc Interference-free proteome quantification with MS/MS-based isobaric isotopologue detection
    Casimir Bamberger
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, California 92037, United States
    J Proteome Res 13:1494-501. 2014
  2. pmc A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats
    Silke Nuber
    Department of Neurosciences, University of California, San Diego, Medical Teaching Facility, Room 346, 9500 Gilman Drive, MC 0624, La Jolla, CA 92093, USA
    Brain 136:412-32. 2013
  3. pmc Phospholipase C epsilon links G protein-coupled receptor activation to inflammatory astrocytic responses
    Stephanie S Dusaban
    Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA
    Proc Natl Acad Sci U S A 110:3609-14. 2013
  4. pmc Immunotherapy for neurodegenerative diseases: focus on α-synucleinopathies
    Elvira Valera
    Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
    Pharmacol Ther 138:311-22. 2013
  5. pmc In vivo quantitative proteomics of somatosensory cortical synapses shows which protein levels are modulated by sensory deprivation
    Margaret T Butko
    Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
    Proc Natl Acad Sci U S A 110:E726-35. 2013
  6. pmc Age-dependent molecular alterations in the autophagy pathway in HIVE patients and in a gp120 tg mouse model: reversal with beclin-1 gene transfer
    Jerel Fields
    Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA
    J Neurovirol 19:89-101. 2013
  7. pmc Axonopathy in an α-synuclein transgenic model of Lewy body disease is associated with extensive accumulation of C-terminal-truncated α-synuclein
    Dora Games
    Neotope Biosciences, South San Francisco, California, USA
    Am J Pathol 182:940-53. 2013
  8. pmc Time course and progression of wild type α-synuclein accumulation in a transgenic mouse model
    David Amschl
    QPS Austria GmbH, Parkring 12, Grambach 8074, Austria
    BMC Neurosci 14:6. 2013
  9. pmc Proteomics of Pyrococcus furiosus (Pfu): Identification of Extracted Proteins by Three Independent Methods
    Catherine C L Wong
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, SR 11, La Jolla, California 92037, USA
    J Proteome Res 12:763-70. 2013
  10. pmc The revolution and evolution of shotgun proteomics for large-scale proteome analysis
    John R Yates
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines, SR11, LaJolla, California 92037, United States
    J Am Chem Soc 135:1629-40. 2013

Research Grants

  1. Expanding the National Health Accounts
    David M Cutler; Fiscal Year: 2013
  2. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013

Detail Information

Publications44

  1. pmc Interference-free proteome quantification with MS/MS-based isobaric isotopologue detection
    Casimir Bamberger
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, California 92037, United States
    J Proteome Res 13:1494-501. 2014
    ..The approach enables precise quantification of a proteome down to single spectra per protein and quantifies >90% of proteins in a MudPIT experiment and accurately measures proteins in a model cell line for cystic fibrosis. ..
  2. pmc A progressive dopaminergic phenotype associated with neurotoxic conversion of α-synuclein in BAC-transgenic rats
    Silke Nuber
    Department of Neurosciences, University of California, San Diego, Medical Teaching Facility, Room 346, 9500 Gilman Drive, MC 0624, La Jolla, CA 92093, USA
    Brain 136:412-32. 2013
    ..Importantly, the observed pathological changes were associated with severe loss of the dopaminergic integrity, thus resembling more closely the human pathology...
  3. pmc Phospholipase C epsilon links G protein-coupled receptor activation to inflammatory astrocytic responses
    Stephanie S Dusaban
    Department of Pharmacology, School of Medicine, University of California at San Diego, La Jolla, CA 92093, USA
    Proc Natl Acad Sci U S A 110:3609-14. 2013
    ..Thus, PLCε links GPCRs to sustained PKD activation, providing a means for GPCR ligands that couple to RhoA to induce NF-κB signaling and promote neuroinflammation...
  4. pmc Immunotherapy for neurodegenerative diseases: focus on α-synucleinopathies
    Elvira Valera
    Department of Neurosciences, University of California, San Diego, La Jolla, CA 92093, USA
    Pharmacol Ther 138:311-22. 2013
    ..In this manuscript we provide an overview on immunotherapeutic advances for neurodegenerative disorders, with special emphasis on α-synucleinopathies...
  5. pmc In vivo quantitative proteomics of somatosensory cortical synapses shows which protein levels are modulated by sensory deprivation
    Margaret T Butko
    Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA
    Proc Natl Acad Sci U S A 110:E726-35. 2013
    ..These data demonstrate the feasibility of defining synaptic proteomes under different sensory rearing conditions and could be applied to elucidate further molecular mechanisms of sensory development...
  6. pmc Age-dependent molecular alterations in the autophagy pathway in HIVE patients and in a gp120 tg mouse model: reversal with beclin-1 gene transfer
    Jerel Fields
    Department of Pathology, University of California San Diego, La Jolla, CA 92093, USA
    J Neurovirol 19:89-101. 2013
    ..These data indicate differential alterations in the autophagy pathway in young versus aged HIVE patients and that autophagy reactivation may ameliorate the neurodegenerative phenotype in these patients...
  7. pmc Axonopathy in an α-synuclein transgenic model of Lewy body disease is associated with extensive accumulation of C-terminal-truncated α-synuclein
    Dora Games
    Neotope Biosciences, South San Francisco, California, USA
    Am J Pathol 182:940-53. 2013
    ..These results show that neuritic dystrophy is a prominent pathologic feature of the mThy1-α-syn tg model and suggest that CT α-syn might play an important role in the process of axonal damage in these mice as well as in DLB and PD...
  8. pmc Time course and progression of wild type α-synuclein accumulation in a transgenic mouse model
    David Amschl
    QPS Austria GmbH, Parkring 12, Grambach 8074, Austria
    BMC Neurosci 14:6. 2013
    ..For this purpose we investigated the time course of behavioral deficits and neuropathology in PDGF-β human wild type α-Syn transgenic mice (D-Line) between 3 and 12 months of age...
  9. pmc Proteomics of Pyrococcus furiosus (Pfu): Identification of Extracted Proteins by Three Independent Methods
    Catherine C L Wong
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, SR 11, La Jolla, California 92037, USA
    J Proteome Res 12:763-70. 2013
    ....
  10. pmc The revolution and evolution of shotgun proteomics for large-scale proteome analysis
    John R Yates
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines, SR11, LaJolla, California 92037, United States
    J Am Chem Soc 135:1629-40. 2013
    ..The use of mass spectrometry for proteome analysis was driven by disruptive innovations that created a capability for large-scale analysis of proteins and modifications...
  11. pmc Microglia promote learning-dependent synapse formation through brain-derived neurotrophic factor
    Christopher N Parkhurst
    Molecular Neurobiology Program, The Kimmel Center for Biology and Medicine at the Skirball Institute, Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY 10016, USA
    Cell 155:1596-609. 2013
    ..Together, our findings reveal that microglia serve important physiological functions in learning and memory by promoting learning-related synapse formation through BDNF signaling. ..
  12. ncbi Structural diversity of Alzheimer's disease amyloid-β dimers and their role in oligomerization and fibril formation
    Igor F Tsigelny
    San Diego Supercomputer Center, University of California, San Diego, La Jolla, CA, USA Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA Department of Neurosciences, University of California, San Diego, La Jolla, CA, USA
    J Alzheimers Dis 39:583-600. 2014
    ..Our studies suggest a greater diversity of Aβ dimers. Understanding the structure of Aβ dimers might be important for the rationale design of small molecules that block formation of toxic oligomers. ..
  13. pmc Identification of GABA(C) receptor protein homeostasis network components from three tandem mass spectrometry proteomics approaches
    Ya Juan Wang
    Center for Proteomics and Bioinformatics and Department of Epidemiology and Biostatistics and Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 10900 Euclid Avenue, Cleveland, Ohio 44106, United States
    J Proteome Res 12:5570-86. 2013
    ..Manipulating selected GABA(C) receptor proteostasis network components is a promising strategy to regulate GABA(C) receptor folding, trafficking, degradation and thus function to ameliorate related retinal diseases...
  14. ncbi Formation of gelsolin amyloid fibrils in the rough endoplasmic reticulum of skeletal muscle in the gelsolin mouse model of inclusion body myositis: comparative analysis to human sporadic inclusion body myositis
    Sergei I Bannykh
    Department of Pathology and Laboratory Medicine, Cedars Sinai Medical Center, Los Angeles, California, USA
    Ultrastruct Pathol 37:304-11. 2013
    ..The study demonstrates a presence of gelsolin amyloid deposits within the rough endoplasmic reticulum. It further compares this mouse model to human sporadic inclusion body myositis...
  15. pmc Identification of long-lived proteins reveals exceptional stability of essential cellular structures
    Brandon H Toyama
    Molecular and Cell Biology Laboratory, Salk Institute for Biological Studies, La Jolla, CA 92037, USA
    Cell 154:971-82. 2013
    ..Our identification of a long-lived proteome reveals cellular components that are at increased risk for damage accumulation, linking long-term protein persistence to the cellular aging process. PAPERCLIP: ..
  16. pmc Surface adsorption considerations when working with amyloid fibrils in multiwell plates and Eppendorf tubes
    Amber N Murray
    Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, 92037 Department of Molecular and Experimental Medicine and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California, 92037
    Protein Sci 22:1531-41. 2013
    ..We apologize for misinterpreting our previous data and for any confounding experimental efforts this may have caused. ..
  17. pmc Energy dependence of HCD on peptide fragmentation: stepped collisional energy finds the sweet spot
    Jolene K Diedrich
    Department of Chemical Physiology, The Scripps Research Institute, La Jolla, CA, 92037, USA
    J Am Soc Mass Spectrom 24:1690-9. 2013
    ..Stepped HCD is also beneficial for tandem mass tagged (TMT) experiments, increasing intensity of TMT reporters used for quantitation without adversely effecting peptide identification. ..
  18. pmc Diversity in the origins of proteostasis networks--a driver for protein function in evolution
    Evan T Powers
    Department of Chemistry, The Scripps Research Institute, La Jolla, California 92037, USA
    Nat Rev Mol Cell Biol 14:237-48. 2013
    ....
  19. pmc Neuron-released oligomeric α-synuclein is an endogenous agonist of TLR2 for paracrine activation of microglia
    Changyoun Kim
    Department of Biomedical Science and Technology, Konkuk University, Seoul 143 701, Republic of Korea
    Nat Commun 4:1562. 2013
    ....
  20. pmc A novel Rac1 GAP splice variant relays poly-Ub accumulation signals to mediate Rac1 inactivation
    Timothy Y Huang
    Department of Immunobiology and Microbial Science, Scripps Research Institute, La Jolla, CA 92037, USA
    Mol Biol Cell 24:194-209. 2013
    ..These results suggest that BGIN/poly-Ub interactions enhance BGIN membrane distribution and relay poly-Ub signals to enact Rac1 inactivation, and attenuation of Rac1 signaling is partially dependent on BGIN in a proteotoxic APP context...
  21. pmc Comparison of protein expression ratios observed by sixplex and duplex TMT labeling method
    Navin Rauniyar
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, USA
    J Proteome Res 12:1031-9. 2013
    ....
  22. ncbi Identification of MOAG-4/SERF as a regulator of age-related proteotoxicity
    Tjakko J van Ham
    Department of Genetics, University Medical Centre Groningen, University of Groningen, Hanzeplein 1, 9700 RB Groningen, The Netherlands
    Cell 142:601-12. 2010
    ..Our results suggest that MOAG-4/SERF regulates age-related proteotoxicity through a previously unexplored pathway, which will open up new avenues for research on age-related, neurodegenerative diseases...
  23. pmc Discovery and characterization of a mammalian amyloid disaggregation activity
    Amber N Murray
    Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA
    Protein Sci 19:836-46. 2010
    ..Identification and manipulation of the proteins responsible for the amyloid disaggregation/degradation activities offers the possibility of ameliorating aggregation-associated diseases...
  24. pmc Reduced IGF-1 signaling delays age-associated proteotoxicity in mice
    Ehud Cohen
    Howard Hughes Medical Institute, Glenn Center for Aging Research, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA
    Cell 139:1157-69. 2009
    ....
  25. pmc Temporal requirements of insulin/IGF-1 signaling for proteotoxicity protection
    Ehud Cohen
    Howard Hughes Medical Institute, Glenn Center for Aging Research, The Salk Institute for Biological Studies, La Jolla, CA 92037, USA
    Aging Cell 9:126-34. 2010
    ....
  26. pmc Reduced histone deacetylase 7 activity restores function to misfolded CFTR in cystic fibrosis
    Darren M Hutt
    Department of Cell Biology, The Scripps Research Institute, La Jolla, California, USA
    Nat Chem Biol 6:25-33. 2010
    ..We suggest that the tunable capacity of HDACs can be manipulated by chemical biology to counter the onset of cystic fibrosis and other human misfolding disorders...
  27. pmc A kinetic assessment of the C. elegans amyloid disaggregation activity enables uncoupling of disassembly and proteolysis
    Jan Bieschke
    Department of Chemistry, The Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, California 92037, USA
    Protein Sci 18:2231-41. 2009
    ..Future discovery of the molecular basis of the disaggregation and proteolysis activities offers the promise of delaying the age-onset proteotoxicity that leads to neurodegeneration in a spectrum of maladies...
  28. ncbi Biological and chemical approaches to diseases of proteostasis deficiency
    Evan T Powers
    Departments of Chemistry and Molecular and Experimental Medicine and the Skaggs Institute for Chemical Biology, The Scripps Research Institute, La Jolla, CA 92037, USA
    Annu Rev Biochem 78:959-91. 2009
    ..We propose that such therapeutic strategies, including combination therapies, represent a new approach for treating a range of diverse human maladies...
  29. pmc Neuropeptide Y fragments derived from neprilysin processing are neuroprotective in a transgenic model of Alzheimer's disease
    John B Rose
    Department of Neurosciences, University of California, San Diego, La Jolla, California 92093 0624, USA
    J Neurosci 29:1115-25. 2009
    ..This function of NEP represents a unique example of a proteolytic enzyme with dual action, namely, degradation of Abeta as well as processing of NPY...
  30. pmc A kinetic aggregation assay allowing selective and sensitive amyloid-β quantification in cells and tissues
    Deguo Du
    Howard Hughes Medical Institute, Molecular and Cell Biology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, United States
    Biochemistry 50:1607-17. 2011
    ..An ion-exchange resin amyloid isolation strategy from complex biological samples is demonstrated as an alternative for improving the sensitivity and linearity of the kinetic aggregation assay...
  31. pmc Lifespan extension induced by AMPK and calcineurin is mediated by CRTC-1 and CREB
    William Mair
    The Salk Institute for Biological Studies, La Jolla, California 92037, USA
    Nature 470:404-8. 2011
    ....
  32. pmc Alzheimer brain-derived amyloid β-protein impairs synaptic remodeling and memory consolidation
    Gilyana G Borlikova
    Laboratory for Neurodegenerative Research, School of Biomolecular and Biomedical Science, Conway Institute, University College Dublin, Dublin, Republic of Ireland
    Neurobiol Aging 34:1315-27. 2013
    ....
  33. ncbi Cerebrolysin modulates pronerve growth factor/nerve growth factor ratio and ameliorates the cholinergic deficit in a transgenic model of Alzheimer's disease
    Kiren Ubhi
    Department of Neurosciences, University of California San Diego, La Jolla, California 92093 0624, USA
    J Neurosci Res 91:167-77. 2013
    ..These results suggest that the neurotrophic effects of CBL might involve modulation of the pro-NGF/NGF balance and a concomitant protection of cholinergic neurons...
  34. ncbi Alzheimer's disease: recent advances and future perspectives
    Kiren Ubhi
    Department of Neurosciences, University of California, San Diego, CA 92093 0624, USA
    J Alzheimers Dis 33:S185-94. 2013
    ..This review will summarize the main areas of investigation in AD and present ways forward for future work...
  35. pmc Proteomic analysis of wild-type and mutant huntingtin-associated proteins in mouse brains identifies unique interactions and involvement in protein synthesis
    Brady P Culver
    Department of Microbiology, New York University School of Medicine, New York, New York 10016, USA
    J Biol Chem 287:21599-614. 2012
    ..Cumulatively, these data support a new role for Htt in translation and provide impetus for further study into the link between protein synthesis and Huntington disease pathogenesis...
  36. pmc Lentivirus mediated delivery of neurosin promotes clearance of wild-type α-synuclein and reduces the pathology in an α-synuclein model of LBD
    Brian Spencer
    Department of Neurosciences, University of California, San Diego, La Jolla, California 92093 0624, USA
    Mol Ther 21:31-41. 2013
    ..Therefore, viral vector driven expression of neurosin may warrant further investigation as a potential therapeutic tool for DLB...
  37. ncbi Temporal requirements of heat shock factor-1 for longevity assurance
    Yuli Volovik
    Biochemistry and Molecular Biology, The Institute for Medical Research Israel Canada IMRIC, The Hebrew University Hadassah Faculty of Medicine, Ein Karem, Jerusalem 91120, Israel
    Aging Cell 11:491-9. 2012
    ..This study proposes a novel link between HSF-1 and the longevity functions of the IIS...
  38. pmc Extremely long-lived nuclear pore proteins in the rat brain
    Jeffrey N Savas
    Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Science 335:942. 2012
    ..Thus, it is possible that failure to maintain proper levels and functional integrity of ELLPs in nonproliferative cells might contribute to age-related deterioration in cell and tissue function...
  39. pmc Proteostasis: a new therapeutic paradigm for pulmonary disease
    Marion Bouchecareilh
    Department of Cell Biology, The Skaggs Institute for Chemical Biology, La Jolla, CA 92037, USA
    Proc Am Thorac Soc 8:189-95. 2011
    ....
  40. pmc The fold of alpha-synuclein fibrils
    Marçal Vilar
    The Salk Institute for Biological Studies, North Torrey Pines Road, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 105:8637-42. 2008
    ..5 nm. Based on the combination of these data and published structural studies, a fold of alpha-syn in the fibrils is proposed and discussed...

Research Grants30

  1. Expanding the National Health Accounts
    David M Cutler; Fiscal Year: 2013
    ..Establishment of a set of national health accounts will allow us as a society to understand which medical interventions improve the health of the U.S. population most efficiently. ..
  2. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..