Research Summary

The McConlogue laboratory focuses on both understanding the mechanisms involved in neurodegeneration driven by misfolding-prone proteins and in developing therapeutic approaches to treat neurological diseases such as Alzheimer's and Parkinson's diseases (AD and PD) and Lewy body dementias (LBD). We are particularly interested in understanding the pathogenic role and functional perturbation of intrinsically disordered proteins (IDP) that, due to their unique structural characteristics and key functional roles, lead to diseases of amyloid-type misfolding including cancer and neurodegenerative diseases.

Our current focus is on understanding and blocking the pathogenic processes of alpha-Synuclein (a-Syn), an IDP that plays a central role in PD and LBD and also contributes to AD. Specifically we are identifying both small molecule and cellular chaperones that protect against a-Syn pathogenicity and investigating their mechanisms of action. We have identified a novel action of the cellular chaperone Hsp70 preventing pathogenic a-Syn misfolding using a non-canonical Hsp70 engagement site. This discovery could lead to therapies for AD, PD and LBD specifically targeting Hsp70 to a-Syn without perturbing the myriad of essential proteins that are canonical substrates of Hsp70.

Research Funding

  • August 1, 2015 - July 31, 2017 - Small-Molecule Pharmacological Chaperones to Prevent Synuclein Transmission, Principal Investigator. Sponsor: NIH/NINDS, Sponsor Award ID: R21NS092897
  • August 1, 2015 - July 31, 2017 - Small-Molecule Pharmacological Chaperones to Prevent Synuclein Transmission, Principal Investigator. Sponsor: NIH/NINDS, Sponsor Award ID: R21NS092897
  • August 1, 2015 - July 31, 2017 - Small-Molecule Pharmacological Chaperones to Prevent Synuclein Transmission, Principal Investigator. Sponsor: NIH/NINDS, Sponsor Award ID: R21NS092897
  • August 1, 2015 - July 31, 2017 - Small-Molecule Pharmacological Chaperones to Prevent Synuclein Transmission, Principal Investigator. Sponsor: NIH/NINDS, Sponsor Award ID: R21NS092897

Education

University of California, Los Angeles, B.A., 1973, Mathematics
University of California, Los Angeles, M.S., 1975, Medical Physics
University of California, Los Angeles, Ph.D., 1978, Medical Physics
University of California, San Francisco, Postdoctoral, 1985, Somatic Cell Genetics

Selected Publications

  1. Tao J, Berthet A, Citron YR, Tsiolaki PL, Stanley R, Gestwicki JE, Agard DA, McConlogue L. Hsp70 chaperone blocks a-synuclein oligomer formation via a novel engagement mechanism. J Biol Chem. 2021 Jan-Jun; 296:100613.  View on PubMed
  2. Tóth G, Neumann T, Berthet A, Masliah E, Spencer B, Tao J, Jobling MF, Gardai SJ, Bertoncini CW, Cremades N, Bova M, Ballaron S, Chen XH, Mao W, Nguyen P, Tabios MC, Tambe MA, Rochet JC, Junker HD, Schwizer D, Sekul R, Ott I, Anderson JP, Szoke B, Hoffman W, Christodoulou J, Yednock T, Agard DA, Schenk D, McConlogue L. Novel Small Molecules Targeting the Intrinsically Disordered Structural Ensemble of a-Synuclein Protect Against Diverse a-Synuclein Mediated Dysfunctions. Sci Rep. 2019 11 18; 9(1):16947.  View on PubMed
  3. Pickhardt M, Neumann T, Schwizer D, Callaway K, Vendruscolo M, Schenk D, St George-Hyslop P, Mandelkow EM, Dobson CM, McConlogue L, Mandelkow E, Tóth G. Identification of Small Molecule Inhibitors of Tau Aggregation by Targeting Monomeric Tau As a Potential Therapeutic Approach for Tauopathies. Curr Alzheimer Res. 2015; 12(9):814-28.  View on PubMed
  4. Tóth G, Gardai SJ, Zago W, Bertoncini CW, Cremades N, Roy SL, Tambe MA, Rochet JC, Galvagnion C, Skibinski G, Finkbeiner S, Bova M, Regnstrom K, Chiou SS, Johnston J, Callaway K, Anderson JP, Jobling MF, Buell AK, Yednock TA, Knowles TP, Vendruscolo M, Christodoulou J, Dobson CM, Schenk D, McConlogue L. Targeting the intrinsically disordered structural ensemble of a-synuclein by small molecules as a potential therapeutic strategy for Parkinson's disease. PLoS One. 2014; 9(2):e87133.  View on PubMed
  5. Gardai SJ, Mao W, Schüle B, Babcock M, Schoebel S, Lorenzana C, Alexander J, Kim S, Glick H, Hilton K, Fitzgerald JK, Buttini M, Chiou SS, McConlogue L, Anderson JP, Schenk DB, Bard F, Langston JW, Yednock T, Johnston JA. Elevated alpha-synuclein impairs innate immune cell function and provides a potential peripheral biomarker for Parkinson's disease. PLoS One. 2013; 8(8):e71634.  View on PubMed
  6. Masliah E, Rockenstein E, Mante M, Crews L, Spencer B, Adame A, Patrick C, Trejo M, Ubhi K, Rohn TT, Mueller-Steiner S, Seubert P, Barbour R, McConlogue L, Buttini M, Games D, Schenk D. Passive immunization reduces behavioral and neuropathological deficits in an alpha-synuclein transgenic model of Lewy body disease. PLoS One. 2011 Apr 29; 6(4):e19338.  View on PubMed
  7. Inglis KJ, Chereau D, Brigham EF, Chiou SS, Schöbel S, Frigon NL, Yu M, Caccavello RJ, Nelson S, Motter R, Wright S, Chian D, Santiago P, Soriano F, Ramos C, Powell K, Goldstein JM, Babcock M, Yednock T, Bard F, Basi GS, Sham H, Chilcote TJ, McConlogue L, Griswold-Prenner I, Anderson JP. Polo-like kinase 2 (PLK2) phosphorylates alpha-synuclein at serine 129 in central nervous system. J Biol Chem. 2009 Jan 30; 284(5):2598-2602.  View on PubMed
  8. McConlogue L, Buttini M, Anderson JP, Brigham EF, Chen KS, Freedman SB, Games D, Johnson-Wood K, Lee M, Zeller M, Liu W, Motter R, Sinha S. Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP Transgenic Mice. J Biol Chem. 2007 Sep 07; 282(36):26326-34.  View on PubMed
  9. Kobayashi D, Zeller M, Cole T, Buttini M, McConlogue L, Sinha S, Freedman S, Morris RG, Chen KS. BACE1 gene deletion: impact on behavioral function in a model of Alzheimer's disease. Neurobiol Aging. 2008 Jun; 29(6):861-73.  View on PubMed
  10. Basi G, Frigon N, Barbour R, Doan T, Gordon G, McConlogue L, Sinha S, Zeller M. Antagonistic effects of beta-site amyloid precursor protein-cleaving enzymes 1 and 2 on beta-amyloid peptide production in cells. J Biol Chem. 2003 Aug 22; 278(34):31512-20.  View on PubMed
  11. Wyss-Coray T, McConlogue L, Kindy M, Schmidt AM, Du Yan S, Stern DM. Key signaling pathways regulate the biological activities and accumulation of amyloid-beta. Neurobiol Aging. 2001 Nov-Dec; 22(6):967-73.  View on PubMed
  12. Roberds SL, Anderson J, Basi G, Bienkowski MJ, Branstetter DG, Chen KS, Freedman SB, Frigon NL, Games D, Hu K, Johnson-Wood K, Kappenman KE, Kawabe TT, Kola I, Kuehn R, Lee M, Liu W, Motter R, Nichols NF, Power M, Robertson DW, Schenk D, Schoor M, Shopp GM, Shuck ME, Sinha S, Svensson KA, Tatsuno G, Tintrup H, Wijsman J, Wright S, McConlogue L. BACE knockout mice are healthy despite lacking the primary beta-secretase activity in brain: implications for Alzheimer's disease therapeutics. Hum Mol Genet. 2001 Jun 01; 10(12):1317-24.  View on PubMed
  13. Wyss-Coray T, Lin C, Yan F, Yu GQ, Rohde M, McConlogue L, Masliah E, Mucke L. TGF-beta1 promotes microglial amyloid-beta clearance and reduces plaque burden in transgenic mice. Nat Med. 2001 May; 7(5):612-8.  View on PubMed
  14. Maltese WA, Wilson S, Tan Y, Suomensaari S, Sinha S, Barbour R, McConlogue L. Retention of the Alzheimer's amyloid precursor fragment C99 in the endoplasmic reticulum prevents formation of amyloid beta-peptide. J Biol Chem. 2001 Jun 08; 276(23):20267-79.  View on PubMed
  15. 41 Gwen Tatsuno, John Anderson , Jin Hong, David A. Agard, Nobuyuki Ota, Sukanto Sinha, Guriqbal Basi, Lisa McConlogue . Alzheimer’s Disease:Advances in Etiology, Pathogenesis and Therapeutics. Functional analysis of β-secretase using mutagenesis and structural homology modeling. 2001; Chapter 74:799-808. .  View on PubMed
  16. Chen G, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB, Morris RG. A learning deficit related to age and beta-amyloid plaques in a mouse model of Alzheimer's disease. Nature. 2000 Dec 21-28; 408(6815):975-9.  View on PubMed
  17. Mucke L, Yu GQ, McConlogue L, Rockenstein EM, Abraham CR, Masliah E. Astroglial expression of human alpha(1)-antichymotrypsin enhances alzheimer-like pathology in amyloid protein precursor transgenic mice. Am J Pathol. 2000 Dec; 157(6):2003-10.  View on PubMed
  18. Mucke L, Masliah E, Yu GQ, Mallory M, Rockenstein EM, Tatsuno G, Hu K, Kholodenko D, Johnson-Wood K, McConlogue L. High-level neuronal expression of abeta 1-42 in wild-type human amyloid protein precursor transgenic mice: synaptotoxicity without plaque formation. J Neurosci. 2000 Jun 01; 20(11):4050-8.  View on PubMed
  19. Sinha S, Anderson J, John V, McConlogue L, Basi G, Thorsett E, Schenk D. Recent advances in the understanding of the processing of APP to beta amyloid peptide. Ann N Y Acad Sci. 2000; 920:206-8.  View on PubMed
  20. Sinha S, Anderson JP, Barbour R, Basi GS, Caccavello R, Davis D, Doan M, Dovey HF, Frigon N, Hong J, Jacobson-Croak K, Jewett N, Keim P, Knops J, Lieberburg I, Power M, Tan H, Tatsuno G, Tung J, Schenk D, Seubert P, Suomensaari SM, Wang S, Walker D, Zhao J, McConlogue L, John V. Purification and cloning of amyloid precursor protein beta-secretase from human brain. Nature. 1999 Dec 02; 402(6761):537-40.  View on PubMed

Go to UCSF Profiles, powered by CTSI