Ai Yamamoto, PhD

Profile Headshot

Overview

Academic Appointments

  • Associate Professor of Neurology
  • Associate Professor of Pathology & Cell Biology

Gender

  • Female

Credentials & Experience

Education & Training

  • BS, 1994 Material Science and Engineering, Massachusetts Institute of Technology
  • PhD, 2002 Columbia University, New York, NY

Research

The overriding theme of our research is to examine the molecular mechanism of protein trafficking events that modulate neural function and neurodegeneration. Our studies have focused on two forms of protein trafficking, one that mediates elimination of abnormal cellular proteins and a second that modulates the function of normal cellular proteins. In the former case we seek to understand how protein cargoes implicated in degenerative diseases are selected for degradation by the macroautophagy pathway, and are currently exploring how selective and basal macroautophagic processes are regulated in the healthy and diseased brain.  In the latter case, our goal is to identify how cholesterol rich membrane microdomains modulate the function of membrane proteins such as neurotransmitter transporters, and how this impacts neurotransmission. 

The strategy underlying our work begins with fundamental biochemical and cell biological approaches to identify the key molecular regulators of a protein trafficking event. Our goal is to apply these findings to the developing and adult brain using mouse genetics, to determine if modulating our pathway of interest can modify disease states. Transitioning our cell-based findings into the correct environmental context is critical; the highly specialized nature of neural cell types can lead to unexpected adaptations of a cellular pathway. Moreover, the cellular needs of an embryonic brain may be quite distinct from an aging one. These hypotheses driven studies in mice then inform us how we can further interpret our cell based work in the context of neural function, and importantly, how we can apply our findings to disease.

Research Interests

  • Roles of macroautophagy in the healthy and diseased CNS
  • Neural Degeneration and Repair
  • Disease
  • Protein trafficking

Grants

MODULATING SELECTIVE AUTOPHAGY TO MODIFY HUNTINGTON S DISEASE (Federal Gov)

Apr 15 2019 - Mar 31 2024

SELECTIVE AUTOPHAGY IN PARKINSON S DISEASE (Federal Gov)

Jul 1 2018 - Mar 31 2023

AUTOPHAGY AND NEURODEGENERATION (Federal Gov)

Apr 1 2015 - Mar 31 2021

ABERRATIONS IN AUTOPHAGY IN THE HUMAN BRAIN OF HUNTINGTON S DISEASE: A POST-MORTEM STUDY WITH CORRELATION TO MURINE MODELS (Private)

Dec 3 2018 - Dec 2 2020

GENERATION OF STRIATAL NEURONS FROM HD PATIENT-DERIVED FIBROBLASTS: A FEASIBILITY STUDY WITH DIRECT CORRELATION TO HUMAN NEUROPATHOLOGY (Private)

Sep 1 2019 - Aug 31 2020

IDENTIFICATION OF THE INITIAL CELLULAR SITE OF ACTION OF A-SYNUCLEIN IN THE PATHOGENESIS OF PARKINSON S DISEASE IN VIVO. (Federal Gov)

Jul 1 2017 - Jun 30 2019

SELECTIVE AUTOPHAGY AND ALS (Private)

Jan 1 2017 - Dec 31 2018

SERVICE AGREEMENT: NPT088 EUREKA IGG1 NEGATIVE CONTROL (CATALOGUE # ET901) PBS (P&S Industry Clinical Trial)

Aug 28 2013 - Aug 28 2018

ALFY-MEDIATED DEGRADATION AND HD (Private)

Jan 20 2017 - Jan 19 2018

CELLULAR MECHANISMS CONTROLLING WHITE MATTER CONNECTIVITY: MAKING SENSE OF A GENETIC RISK FACTOR FOR AUTISM AND SCHIZOPHERNIA (Private)

Jan 15 2016 - Jan 14 2018

PARKINSON S DISEASE FOUNDATION (PDF) RESEARCH CENTER GRANT (Private)

Jul 1 2016 - Jun 30 2017

ALFY-MEDIATED DEGRADATION AND HD (Private)

Mar 1 2016 - Feb 28 2017

PARKINSONS DISEASE FOUNDATION RESEARCH CENTER GRANT (Private)

Jul 1 2000 - Jun 30 2016

ALFY-MEDIATED SELECTIVE MACROAUTOPHAGY AND THE PATHOGENESIS OF HUNTINGTON S DISEASE (Federal Gov)

Sep 1 2013 - Aug 31 2015

PARKINSONS DISEASE FOUNDATION RESEARCH CENTER GRANT (Private)

Jul 1 2000 - Jun 30 2015

STRUCTURE AND FUNCTION OF NEUROTRANSMITTER TRANSPORTERS (Federal Gov)

Mar 1 2011 - Feb 28 2015

PARKINSON S DISEASE FOUNDATION RESEARCH CENTE (Private)

Jul 1 2000 - Jun 30 2014

PARKINSON S DISEASE FOUNDATION RESEARCH CENTE (Private)

Jul 1 2000 - Jun 30 2014

PARKINSONS DISEASE FOUNDATION (PDF) RESEARCH CENTER GRANT 2012-2013 (Private)

Jul 1 2009 - Jun 30 2013

PARKINSONS DISEASE FOUNDATION (PDF) RESEARCH CENTER GRANT 20 11-2012 (Private)

Jul 1 2009 - Jun 30 2013

STRUCTURE AND FUNCTION OF NEUROTRANSMITTER TRANSPORTERS (Federal Gov)

Mar 1 2011 - Feb 28 2013

CAN THE INHIBITION OF FARNESYLATION POSITIVELY MODIFY THE CL EARANCE OF EXPANDED POLYGLUTAMINE INCLUSIONS? (Private)

Oct 1 2010 - Dec 31 2011

PROTEIN TRAFFICKING IN NEURODEGENERATIVE DISEASES (Federal Gov)

Sep 30 2009 - Aug 31 2011

Selected Publications

Dragich, J.M., Kuwajima, T., Hirose-Ikeda, M., Yoon, M.S., Eenjes, E., Bosco, J.R., Fox, L.M., Lystad, A.H., Oo, T.F., Yarygina, O., Mita, T., Waguri, S., Ichimura, Y., Komatsu, M., Simonsen, A., Burke, R.E., Mason, C.A. and Yamamoto, A. (2016) eLife. Autophagy linked FYVE (Alfy/WDFY3) is required for establishing neuronal connectivity in the mammalian brain. 5: e14810

Eenjes, E., Dragich, J.M., Kampinga, H.H. and Yamamoto, A. Distinguishing aggregate formation versus aggregate clearance using cell based assays. (2016) J Cell Sci  129(6): 1260-1270.

Yamamoto, A. and Yue, Z.-Y. (2014) Autophagy and its Normal and Pathogenic States in the brain. Ann Rev Neurosci. 37:55-78.

Nath, S., Puente, P., Dancourt, J., Fong, W., Nag, S., Yamamoto, A., Antonny, B., Melia, T.J. (2014) Lipidation of the autophagy protein LC3 is a membrane curvature-dependent process. Nat Cell Biol. 16(5): 415-424. PMC24747438

Cremona, M.L., Matties, H.J.G., Bowton, E., Speed, N., Lute, B.J., Pau, K., Anderson, M.A.,  Sen, N., Doughty, S.E., Rothman, J.E., Galli, A., Javitch, J.A. and Yamamoto, A. (2011) Flotillin-1 is essential for dopamine transporter endocytosis and reverse-transport of dopamine. Nat. Neurosci. 14:469-477.

Yamamoto, A. and Simonsen, A. (2011) The elimination of accumulated and aggregated proteins: A role for aggrephagy in neurodegeneration. Neurobiol. Dis.43:17-28

Filimonenko, M., Isakson, P., Finley, K.D., Anderson, M., Melia, Jr., Jeong, H., T.J., Bartlett, B.J., Myers, K.M.,  Birkeland, H.C.G., Lamark, T., Krainc, D., Brech, A., Stenmark, H., Simonsen, A. and Yamamoto, A. (2010) The selective macroautophagic degradation of aggregated proteins requires the PI3-P binding protein, Alfy. Molecular Cell 2: 265-279