Aimee Kao, MD, PhD | Neuroscience Graduate Program

Associate Professor

M_Neurology

415-502-7123

The molecular mechanisms underlying neurodegenerative disease

Neurodegenerative diseases are fundamentally the result of aberrant proteostasis within neurons. My lab is interested in understanding the basic cell and molecular changes leading to this aberrant proteostasis in Alzheimer Disease, frontotemporal lobar degeneration and other neurodegenerative conditions. In particular, we are focused on the consequences of impaired autophagy and lysosomal function. The lysosome is not only the cell’s garbage can—rather, it is a central regulator of homeostasis, responsible for protein and lipid recycling, amino acid storage, appropriate stress response and regulated cell growth. We have shown that mutations responsible for neurodegenerative diseases can directly alter lysosome function with pleotropic downstream consequences. Our current work utilizes C. elegans, induced pluripotent stem cells (iPSC) and other cellular models to decipher how alterations in lysosome function, autophagy, cell and organelle pH and stress response programs can lead to neuronal dysfunction and death.

Current Projects

Lysosomes, Aging and Neurodegenerative Disease
Progranulin and Prosaposin in regulating lysosomal function
Tau, TSC1 and mTOR activity
New disease mechanisms for autosomal dominant mutations in alpha-synuclein, TDP-43 and Tau
pH regulation and dysregulation in aging and disease

Lab Members

Shruti Arya, PhD
Postdoctoral Fellow
[email protected]

Camila Benitez
Tetrad Graduate Student
[email protected]

Virginia Garda
CCB Graduate Student
[email protected]

Molly Hodul, PhD
Postdoctoral Fellow
[email protected]

Courtney Lane-Donovan, MD, PhD
Postdoctoral Fellow
[email protected]

Paul Sampognaro, MD
Clinical Instructor
[email protected]

Andrea Argouarch
Associate Specialist
[email protected]

Austin Wang
Neuroscience Graduate Student
[email protected]

Mackenzie Welch
Neuroscience Graduate Student
[email protected]

Joanne De Torres
Lab Assistant
[email protected]

Lab Website

Academic community service and committee membership:

NS Diversity Co-Chair, NS Formal Seminar Committee, NS Curriculum Committee, NS Student Advisors/Student Progress, First-year advisor, Advise in BM and MSTP, hosted 3 SRTP students, MSTP Executive committee, Neurology Advancement and Promotions, have undergone extensive DEI training

Publications

Lysosomal Protease-Mediated APP Degradation is pH-Dependent, Mutation-Sensitive, and Facilitates Tau Proteolysis.

Research square

Ackley C, Liau Z, Arya S, Antee T, Knudsen GM, Lane-Donovan C, Sampognaro PJ, Kao AW

Tau phosphorylation at Alzheimer's disease biomarker sites impairs its cleavage by lysosomal proteases.

Lane-Donovan C, Smith AW, Saloner R, Miller BL, Casaletto KB, Kao AW

GRAMD1B is a regulator of lipid homeostasis, autophagic flux and phosphorylated tau.

Acosta Ingram D, Turkes E, Kim TY, Vo S, Sweeney N, Bonte MA, Rutherford R, Julian DL, Pan M, Marsh J, Argouarch AR, Wu M, Scharre DW, Bell EH, Honig LS, Vonsattel JP, Serrano GE, Beach TG, Karch CM, Kao AW, Hester ME, Han X, Fu H

The relationship between caloric intake and clinical outcomes in critically ill patients: A retrospective study.

Lin YR, Chen PC, Li WT, Huang MH, Huang SF, Wang CJ, Chien YW, Kao AW, Shan YS

mTOR activation induces endolysosomal remodeling and nonclassical secretion of IL-32 via exosomes in inflammatory reactive astrocytes.

Leng K, Rooney B, McCarthy F, Xia W, Rose IVL, Bax S, Chin M, Fathi S, Herrington KA, Leonetti M, Kao A, Fancy SPJ, Elias JE, Kampmann M

Second international symposium on the chaperone code, 2023.

Buchner J, Alasady MJ, Backe SJ, Blagg BSJ, Carpenter RL, Colombo G, Gelis I, Gewirth DT, Gierasch LM, Houry WA, Johnson JL, Kang BH, Kao AW, LaPointe P, Mattoo S, McClellan AJ, Neckers LM, Prodromou C, Rasola A, Sager RA, Theodoraki MA, Truman AW, Truttman MC, Zachara NE, Bourboulia D, Mollapour M, Woodford MR

The progranulin cleavage product granulin 3 exerts a dominant negative effect on animal fitness.

Wang AL, Mambou EA, Kao AW

Correction: Mutations in α-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases.

Sampognaro PJ, Arya S, Knudsen GM, Gunderson EL, Sandoval-Perez A, Hodul M, Bowles K, Craik CS, Jacobson MP, Kao AW

Mutations in a-synuclein, TDP-43 and tau prolong protein half-life through diminished degradation by lysosomal proteases.

Sampognaro PJ, Arya S, Knudsen GM, Gunderson EL, Sandoval-Perez A, Hodul M, Bowles K, Craik CS, Jacobson MP, Kao AW

Tuberous sclerosis complex is associated with a novel human tauopathy.

Hwang JL, Perloff OS, Gaus SE, Benitez C, Alquezar C, Cosme CQ, Nana AL, Vatsavayai SC, Ramos EM, Geschwind DH, Miller BL, Kao AW, Seeley WW

Postmortem Human Dura Mater Cells Exhibit Phenotypic, Transcriptomic and Genetic Abnormalities that Impact their Use for Disease Modeling.

Argouarch AR, Schultz N, Yang AC, Jang Y, Garcia K, Cosme CG, Corrales CI, Nana AL, Karydas AM, Spina S, Grinberg LT, Miller B, Wyss-Coray T, Abyzov A, Goodarzi H, Seeley WW, Kao AW

Phenotypic Screening Using High-Content Imaging to Identify Lysosomal pH Modulators in a Neuronal Cell Model.

Chin MY, Ang KH, Davies J, Alquezar C, Garda VG, Rooney B, Leng K, Kampmann M, Arkin MR, Kao AW

TSC1 loss increases risk for tauopathy by inducing tau acetylation and preventing tau clearance via chaperone-mediated autophagy.

Alquezar C, Schoch KM, Geier EG, Ramos EM, Scrivo A, Li KH, Argouarch AR, Mlynarski EE, Dombroski B, DeTure M, Dickson DW, Yokoyama JS, Cuervo AM, Burlingame AL, Schellenberg GD, Miller TM, Miller BL, Kao AW

Processing of progranulin into granulins involves multiple lysosomal proteases and is affected in frontotemporal lobar degeneration.

Mohan S, Sampognaro PJ, Argouarch AR, Maynard JC, Welch M, Patwardhan A, Courtney EC, Zhang J, Mason A, Li KH, Huang EJ, Seeley WW, Miller BL, Burlingame A, Jacobson MP, Kao AW

Genetically Encoded, pH-Sensitive mTFP1 Biosensor for Probing Lysosomal pH.

Chin MY, Patwardhan AR, Ang KH, Wang AL, Alquezar C, Welch M, Nguyen PT, Grabe M, Molofsky AV, Arkin MR, Kao AW

Tau Post-translational Modifications: Dynamic Transformers of Tau Function, Degradation, and Aggregation.

Alquezar C, Arya S, Kao AW

Progranulin Adsorbs to Polypropylene Tubes and Disrupts Functional Assays: Implications for Research, Biomarker Studies, and Therapeutics.

Gururaj S, Sampognaro PJ, Argouarch AR, Kao AW

Association of Cognitive and Behavioral Features Between Adults With Tuberous Sclerosis and Frontotemporal Dementia.

Liu AJ, Staffaroni AM, Rojas-Martinez JC, Olney NT, Alquezar-Burillo C, Ljubenkov PA, La Joie R, Fong JC, Taylor J, Karydas A, Ramos EM, Coppola G, Boxer AL, Rabinovici GD, Miller BL, Kao AW

Heavy metals contaminating the environment of a progressive supranuclear palsy cluster induce tau accumulation and cell death in cultured neurons.

Alquezar C, Felix JB, McCandlish E, Buckley BT, Caparros-Lefebvre D, Karch CM, Golbe LI, Kao AW

Protons in small spaces: Discrete simulations of vesicle acidification.

Singh A, Marcoline FV, Veshaguri S, Kao AW, Bruchez M, Mindell JA, Stamou D, Grabe M

A Comprehensive Resource for Induced Pluripotent Stem Cells from Patients with Primary Tauopathies.

Karch CM, Kao AW, Karydas A, Onanuga K, Martinez R, Argouarch A, Wang C, Huang C, Sohn PD, Bowles KR, Spina S, Silva MC, Marsh JA, Hsu S, Pugh DA, Ghoshal N, Norton J, Huang Y, Lee SE, Seeley WW, Theofilas P, Grinberg LT, Moreno F, McIlroy K, Boeve BF, Cairns NJ, Crary JF, Haggarty SJ, Ichida JK, Kosik KS, Miller BL, Gan L, Goate AM, Temple S

Lifespan-increasing drug nordihydroguaiaretic acid inhibits p300 and activates autophagy.

Tezil T, Chamoli M, Ng CP, Simon RP, Butler VJ, Jung M, Andersen J, Kao AW, Verdin E

Age- and stress-associated C. elegans granulins impair lysosomal function and induce a compensatory HLH-30/TFEB transcriptional response.

Butler VJ, Gao F, Corrales CI, Cortopassi WA, Caballero B, Vohra M, Ashrafi K, Cuervo AM, Jacobson MP, Coppola G, Kao AW

Multi-Granulin Domain Peptides Bind to Pro-Cathepsin D and Stimulate Its Enzymatic Activity More Effectively Than Progranulin in Vitro.

Butler VJ, Cortopassi WA, Gururaj S, Wang AL, Pierce OM, Jacobson MP, Kao AW

Tau/MAPT disease-associated variant A152T alters tau function and toxicity via impaired retrograde axonal transport.

Butler VJ, Salazar DA, Soriano-Castell D, Alves-Ferreira M, Dennissen FJA, Vohra M, Oses-Prieto JA, Li KH, Wang AL, Jing B, Li B, Groisman A, Gutierrez E, Mooney S, Burlingame AL, Ashrafi K, Mandelkow EM, Encalada SE, Kao AW

Progranulin Stimulates the in vitro Maturation of pro-Cathepsin D at Acidic pH.

Butler VJ, Cortopassi WA, Argouarch AR, Ivry SL, Craik CS, Jacobson MP, Kao AW

Tauopathy-Associated PERK Alleles are Functional Hypomorphs that Increase Neuronal Vulnerability to ER Stress.

Yuan SH, Hiramatsu N, Liu Q, Sun XV, Lenh D, Chan P, Chiang K, Koo EH, Kao AS, Litvan I, Lin JH

Regionally specific TSC1 and TSC2 gene expression in tuberous sclerosis complex.

Li Y, Barkovich MJ, Karch CM, Nillo RM, Fan CC, Broce IJ, Tan CH, Cuneo D, Hess CP, Dillon WP, Glenn OA, Glastonbury CM, Olney N, Yokoyama JS, Bonham LW, Miller B, Kao A, Schmansky N, Fischl B, Andreassen OA, Jernigan T, Dale A, Barkovich AJ, Desikan RS, Sugrue LP

The Use of Caenorhabditis elegans to Study Progranulin in the Regulation of Programmed Cell Death and Stress Response.

Hsu TY, Butler VJ, Kao AW

Clinicopathological correlations in behavioural variant frontotemporal dementia.

Perry DC, Brown JA, Possin KL, Datta S, Trujillo A, Radke A, Karydas A, Kornak J, Sias AC, Rabinovici GD, Gorno-Tempini ML, Boxer AL, De May M, Rankin KP, Sturm VE, Lee SE, Matthews BR, Kao AW, Vossel KA, Tartaglia MC, Miller ZA, Seo SW, Sidhu M, Gaus SE, Nana AL, Vargas JNS, Hwang JL, Ossenkoppele R, Brown AB, Huang EJ, Coppola G, Rosen HJ, Geschwind D, Trojanowski JQ, Grinberg LT, Kramer JH, Miller BL, Seeley WW

Linking tuberous sclerosis complex, excessive mTOR signaling, and age-related neurodegeneration: a new association between TSC1 mutation and frontotemporal dementia.

Olney NT, Alquezar C, Ramos EM, Nana AL, Fong JC, Karydas AM, Taylor JB, Stephens ML, Argouarch AR, Van Berlo VA, Dokuru DR, Sherr EH, Jicha GA, Dillon WP, Desikan RS, De May M, Seeley WW, Coppola G, Miller BL, Kao AW

Progranulin, lysosomal regulation and neurodegenerative disease.

Kao AW, McKay A, Singh PP, Brunet A, Huang EJ

Animal models of dementia.

MCP-1 and eotaxin-1 selectively and negatively associate with memory in MCI and Alzheimer's disease dementia phenotypes.

Bettcher BM, Fitch R, Wynn MJ, Lalli MA, Elofson J, Jastrzab L, Mitic L, Miller ZA, Rabinovici GD, Miller BL, Kao AW, Kosik KS, Kramer JH

The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels.

Salazar DA, Butler VJ, Argouarch AR, Hsu TY, Mason A, Nakamura A, McCurdy H, Cox D, Ng R, Pan G, Seeley WW, Miller BL, Kao AW

A shift to organismal stress resistance in programmed cell death mutants.

Judy ME, Nakamura A, Huang A, Grant H, McCurdy H, Weiberth KF, Gao F, Coppola G, Kenyon C, Kao AW

The advantages of frontotemporal degeneration drug development (part 2 of frontotemporal degeneration: the next therapeutic frontier).

Boxer AL, Gold M, Huey E, Hu WT, Rosen H, Kramer J, Gao FB, Burton EA, Chow T, Kao A, Leavitt BR, Lamb B, Grether M, Knopman D, Cairns NJ, Mackenzie IR, Mitic L, Roberson ED, Van Kammen D, Cantillon M, Zahs K, Jackson G, Salloway S, Morris J, Tong G, Feldman H, Fillit H, Dickinson S, Khachaturian ZS, Sutherland M, Abushakra S, Lewcock J, Farese R, Kenet RO, Laferla F, Perrin S, Whitaker S, Honig L, Mesulam MM, Boeve B, Grossman M, Miller BL, Cummings JL

Frontotemporal degeneration, the next therapeutic frontier: molecules and animal models for frontotemporal degeneration drug development.

Boxer AL, Gold M, Huey E, Gao FB, Burton EA, Chow T, Kao A, Leavitt BR, Lamb B, Grether M, Knopman D, Cairns NJ, Mackenzie IR, Mitic L, Roberson ED, Van Kammen D, Cantillon M, Zahs K, Salloway S, Morris J, Tong G, Feldman H, Fillit H, Dickinson S, Khachaturian Z, Sutherland M, Farese R, Miller BL, Cummings J

A neurodegenerative disease mutation that accelerates the clearance of apoptotic cells.

Kao AW, Eisenhut RJ, Martens LH, Nakamura A, Huang A, Bagley JA, Zhou P, de Luis A, Neukomm LJ, Cabello J, Farese RV, Kenyon C

Cognitive and neuropsychiatric profile of the synucleinopathies: Parkinson disease, dementia with Lewy bodies, and multiple system atrophy.

Kao AW, Racine CA, Quitania LC, Kramer JH, Christine CW, Miller BL

Expression of a dominant interfering dynamin mutant in 3T3L1 adipocytes inhibits GLUT4 endocytosis without affecting insulin signaling.

Kao AW, Ceresa BP, Santeler SR, Pessin JE

Inhibition of clathrin-mediated endocytosis selectively attenuates specific insulin receptor signal transduction pathways.

Ceresa BP, Kao AW, Santeler SR, Pessin JE

The 66-kDa Shc isoform is a negative regulator of the epidermal growth factor-stimulated mitogen-activated protein kinase pathway.

Okada S, Kao AW, Ceresa BP, Blaikie P, Margolis B, Pessin JE