Neuronal subtype-specific vulnerability in tauopathies using reprogramming methods in human somatic and stem cells

2014 Pilot Project Read More

Investigators

Principal Investigator: Celeste Karch, PhD (WashU Psychiatry)
Collaborator: Andrew Yoo, PhD (WashU Developmental Biology)

Description

Tauopathies affect more than 6 million people in the US and include Alzheimer’s disease,
progressive supranuclear palsy, and frontotemporal dementia. In a subset of these
diseases, genetic changes in MAPT, the gene that encodes the tau protein, initiate a
cascade of events that leads to tau aggregation and death of neuronal populations in the
brain. Some regions in the central nervous system are routinely affected in tauopathies,
while other regions are spared. The cascade of events that leads to disease and that
underlies cell-type specific vulnerability remains poorly understood. Due to the
complexities of the MAPT gene and its expression patterns, current cell and mouse
models have not resolved the mechanisms by which fully penetrant disease mutations or
risk variants in MAPT disrupt the tau protein and cause disease in a cell-type specific
manner. The primary objective for this pilot grant is to use two cell-fate reprogramming
systems to generate human neurons and to test the feasibility of these experimental
conditions to study tauopathies. Starting from the same human fibroblasts, we will i)
generate neurons differentiated from induced pluripotent stem cells; and ii) use
microRNAs and neural transcription factors to directly convert fibroblasts into neurons.
By enriching the population of neuronal subtypes from the reprogramming conditions, we
hope to understand neuronal subtype-specific vulnerability underlying tauopathies.
Together, this study will use novel human cell models that will begin to define the
cascade of events that lead to neurodegenerative tauopathies and will provide avenues
for advancement in therapeutic intervention.

Publications

Christine J Huh, Bo Zhang, Matheus B Victor, Sonika Dahiya, Luis FZ Batista, Steve Horvath, Andrew S Yoo: Maintenance of age in human neurons generated by microRNA-based neuronal conversion of fibroblasts. eLife ;5:e18648, (2016).

Updated June 2017

Hope Center Investigators

Pilot project teams include Hope Center faculty members and others. For more about Hope Center faculty on this team, click below.

Celeste Karch

Andrew Yoo

Support

This pilot project is made possible by the Danforth Foundation Challenge, and The Hope Center Program on Protein Aggregation and Neurodegeneration (HPAN).

Danforth Challenge

HPAN