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Intracellular and Extracellular Tau as Drivers of Lysosomal Failure in Human Neuronal Models of Frontotemporal Dementia

Award Number: K99NS150834
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 09/10/2026
PERIOD OF PERFORMANCE END DATE: 08/31/2028

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Intracellular and Extracellular Tau as Drivers of Lysosomal Failure in Human Neuronal Models of Frontotemporal Dementia - Project Abstract/Summary Protein aggregation is a hallmark of neurodegenerative diseases, and mounting evidence implicates lysosomal failure as a key driver of proteostasis collapse. However, it remains unknown when lysosomal dysfunction emerges relative to pathology and how it can be effectively targeted. My long-term goal is to establish an independent research program that defines the molecular cascade leading to lysosomal collapse preceding Tau aggregation, to uncover therapeutic targets that can halt or reverse disease progression. In frontotemporal lobar degeneration with Tau inclusions (FTLD-Tau), the microtubule-associated protein Tau, encoded by MAPT, becomes hyperphosphorylated and forms pathological aggregates. Mutations in MAPT cause familial FTLD-Tau, but the mechanisms linking these mutations to lysosomal dysfunction and Tau aggregation remain unclear. Using human induced pluripotent stem cell (iPSC)-derived neurons and super- resolution microscopy, I discovered that phosphorylated Tau (pTau-Thr231) accumulates at the lysosomal membrane, impeding degradation, and that a pathogenic MAPT mutation (R406W) disrupts lysosomal motility, autophagosome-lysosome fusion, and cargo degradation. These defects are rescued by an analog of the FDA- approved drug Glibenclamide, revealing a promising therapeutic avenue. Yet, it remains unknown whether distinct MAPT mutations or Tau post-translational modifications differentially impair lysosomal trafficking and degradation, how these early disruptions initiate Tau aggregation, and how Tau aggregates, in turn, exacerbate lysosomal and autophagic failure. I hypothesize that lysosomal failure occurs upstream of Tau aggregation and is mediated by specific phospho- epitopes of Tau. During the K99 phase, I will gain training in electron microscopy (EM/Cryo-EM) and advanced lysosomal imaging to visualize Tau within lysosomal compartments. In the R00 phase, I will integrate these approaches with my expertise in Tau biology, stem cell modeling, and autophagy to define how Tau aggregates drive lysosomal vulnerability and to test pharmacological rescue strategies. Through this integrated research and mentored training plan, I will uncover fundamental mechanisms of lysosomal impairment in human neurons, establish new experimental platforms for Tau-lysosome biology, and lay the foundation for an independent research program targeting lysosomal pathways in neurodegeneration.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $113,919 )
2026	2026	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	9/9/2026	NEW	$113,919
														Subtotal = $113,919

Grand Total All Awards = $113,919

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Intracellular and Extracellular Tau as Drivers of Lysosomal Failure in Human Neuronal Models of Frontotemporal Dementia

Award Number: K99NS150834

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 09/10/2026

PERIOD OF PERFORMANCE END DATE: 08/31/2028

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