Marc Vermulst
Marc Vermulst - PhD
The New Investigator Awards in Alzheimer's Disease - 2015
Marc Vermulst

Marc Vermulst - PhD

Assistant Professor - Children’s Hospital of Philadelphia
Pennsylvania, United States


The New Investigator Awards in Alzheimer's Disease - 2015

Transcription errors in Alzheimer’s disease

Transcription is required for every biological process inside a cell. Although most transcripts are generated faithfully from their DNA template, errors do occur from time to time. How these errors affect cellular function is unknown.

To answer this question, Dr. Vermulst and his group monitored yeast cells that were genetically engineered to display error-prone transcription. They discovered that these cells suffer from a profound loss in proteostasis (the quality control of their proteins was compromised), which sensitizes them to the expression of genes that are associated with protein-folding diseases in humans. For example, expression of Aβ1-42 (Alzheimer’s disease), TDP-43 (Amyotrophic Lateral Sclerosis), and Htt103 (Huntington’s disease) caused greater protein aggregation and cellular toxicity in the error-prone cells compared to the normal cells. Thus, transcription errors represent a new molecular mechanism by which cells can acquire disease.

Dr. Vermulst’s team further discovered that the error rate of transcription increases with age in yeast, which contributes to the decline in proteostasis seen in aging cells. In humans, a similar age-related increase in the error rate of transcription could allow proteins associated with age-related diseases such as Alzheimer’s disease to accumulate in aging neurons, which would provide valuable new insight into the molecular etiology of Alzheimer’s disease and other age-related diseases. Dr. Vermulst will test this hypothesis in aging mice and human cell lines that display either normal or error-prone transcription.

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