2024 New Investigator Awards Program (NIAP)
Uncovering the Molecular Pathogenesis of Semantic Dementia
What genetic changes take place in a brain disease that hinders one’s ability to communicate?
Malik Nassan, M.D.
Northwestern University
Chicago, IL - United States
Background
Frontotemporal dementias (FTDs) are brain diseases characterized by the early onset of dementia (occurring by one's 40s or 50s) along with changes in personality and emotions and difficulty in understanding language. These diseases impact the brain’s frontal lobes (areas behind your forehead) and temporal lobes (regions behind your ears). FTDs include a group of disorders called primary progressive aphasias (PPAs), which affect language skills, speaking, writing and comprehension. One type of PPA is the “semantic” variation (sPPA), in which individuals lose the ability to understand or formulate language in a spoken sentence.
People with FTDs have abnormal build-up of the protein TAR DNA-binding protein 43 (TDP-43), and sPPA is closely linked with a certain form of TDP-43 called TDP-43 Type C. Studies also show that brain changes associated with sPPA occur primarily in a brain region called the temporal lobe. Scientists, however, still need to determine the specific genetic changes that take place during sPPA. Such knowledge will be necessary to develop effective methods of diagnosing and curing this rare brain disease.
Research Plan
Dr. Malik Nassan and colleagues will devote their research grant to a genetic study of semantic primary progressive aphasia. For this effort, they will examine temporal lobe brain samples of people who had sPPA. Specifically, the researchers will analyze the samples’ genomes (complete sets of genes) and transcriptomes (collections of all gene readouts) to identify gene variations associated with sPPA. They will also study changes in how those genes undergo DNA methylation, a process by which genetic material, or DNA, is modified by the addition of a chemical methyl group. Methylation is used to turn genes “on” and “off” during different phases of the body’s development, and it helps regulate proper gene expression (the conversion of genes into proteins).
Impact
Dr. Malik’s project could shed new light on the genetic underpinnings of sPPA. Such work could lead to genetic strategies, such as gene editing, for treating the disorder. Moreover, if this project is successful, Dr. Malik plans to conduct similar studies with other forms of PPA.
The New Investigator Program Award (NIAP) is jointly funded by the Alzheimer's Association and National Alzheimer’s Coordinating Center.