[DISSERTATION] TBK1 deficiency leads to TDP-43 pathology driven by endo-lysosomal dysfunction in human-induced motor neurons

Author: Hao, J.

Harvard University Graduate School of Arts and Sciences, 2022.

The author used Axion’s next-generation Maestro MEA and other methods to explore the pathogenesis of amyotrophic lateral sclerosis (ALS).

Whole-genome sequencing and whole exome sequencing have shed new light on genetic links to amyotrophic lateral sclerosis (ALS), but the underlying mechanisms are not fully understood. In this dissertation, the author used CRISPR/Cas9 gene editing to generate a human stem cell model carrying TBK1 loss-of-function mutations and explored the pathogenesis of ALS with Axion’s noninvasive, label-free Maestro multielectrode array (MEA) platform and other methods. Overall, the findings demonstrated that TBK1 deficiency and its downstream effects contribute to the development of ALS and found that “restoring TBK1 deficient cells re-sustained endo-lysosomal function and TDP-43 homeostasis and maintained motor neuron physiological functions”—results that may lead the way to the development of new therapeutics for neurodegenerative diseases caused by TBK1 deficiency.