2015

The New Investigator Awards in Alzheimer's Disease


Marc Vermulst, PhD

Assistant Professor, Children’s Hospital of Philadelphia

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.

More 2015 Recipients of this Grant

Todd Cohen, PhD

Novel Post-translational Mechanisms that Mediate Neurodegeneration in Aging and Alzheimer’s Disease

Jason Hinman, MD, PhD

Development of a Novel Mouse Model of Mixed Vascular- and Alzheimer’s -Caused Dementia

Manu Sharma, PhD

Tau Proteostasis by Hsc70 Co-Chaperones

Alon Zaslaver, PhD

Synaptic failure in AD during aging-associated proteostasis collapse