Characterizing a novel amyotrophic lateral sclerosis transgenic mouse carrying a human mutation TDP43(A315T).


Chelsea Culbert

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In: Summer Student Reports, 2011, Jackson Laboratory


Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease resulting in the specific loss of motor neurons in the brain and spinal cord. Most cases of ALS are sporadic while 5-10% of patients are familial in nature. The recent discovery of TDP43 as a key component of ubiquitinated protein aggregates in both sporadic and familial ALS patients has ignited the field of ALS research. TDP43 is known to accumulate in ubiquitinated inclusions of affected neurons, suggesting that the loss of normal TDP43 function as a nuclear protein or, alternatively, a gain of a toxic function by TDP43 aggregates may play a critical role in the pathogenesis. The mechanisms of TDP43 functions are currently being investigated in yeast and transformed cell lines, however, the role of these interactions in disease-relevant cells is not known. To address this, I differentiated embryonic stem (ES) cells, derived from TDP43 transgenic mice carrying the human mutation A315T, into motor neurons and plated both mutant and control embryonic stem cell-derived motor neurons for 7, 14, 21 and 28 days in vitro (DIV). Using immunocytochemistry following 14, 21 and 28 DIV, I found that the TDP43(A315T) ES cell-derived motor neurons contained cytoplasmic inclusions that were positive for TDP43, ubiquitin, and FUS. Interestingly, the cytoplasmic aggregates in mutant ES cell-derived motor neurons were not positive for phosphorylated-TDP43. In addition, there was a significant loss of ES cell-derived motor neurons that expressed TDP43(A315T) compared to controls. In the future, the in vitro assay containing ES cell-derived motor neurons carrying the human ALS mutation will serve as a platform for discovery of biomarkers of both sporadic and familial ALS disease mechanisms and facilitate future ALS drug testing.


NYU, New York, NY

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