2023 Alzheimer's Association Research Fellowship to Promote Diversity (AARF-D)

Defining the Role of Adenylate Kinases in Dementia with Lewy Bodies

How do the brain’s support cells impact the clumping of the protein alpha synuclein?  

Namrata Kumari, Ph.D.
University of Pittsburgh
Pittsburgh, PA - United States

Background

A protein called alpha-synuclein is thought to help in maintaining proper nerve cell communication in the brain. However, misfolded collections of alpha-synuclein within nerve cells (known as Lewy bodies) are hallmarks of neurodegenerative diseases such as Parkinson’s disease and dementia with Lewy bodies (DLB). Lewy bodies is also observed in some individuals with Alzheimer’s. 

Some research suggests that support cells in the brain called astrocytes may play a role in alpha synuclein-related neurodegeneration. Scientists have identified two genes, adenylate kinase 1 (Ak1) and adenylate kinase 2 (Ak2), that appear to have effects on astrocytes. These genes code for proteins that are influence energy balance (bioenergetics) and excitotoxicity (a process in which nerve cells become overstimulated and which can lead to cognitive decline and nerve cell death). Dr. Namrata Kumari and colleagues believe that Ak1 and Ak2 activity in astrocytes may affect Lewy body formation by regulating bioenergetics and excitotoxicity.

Research Plan

The research team will study a genetically engineered fruit fly model of DLB. They will use genetic tools to “turn off” Ak1 and Ak2 and then determine the effects on excitotoxicity. Next, the researchers will “turn off” Ak1 and Ak2 in mouse nerve cells and astrocytes grown in laboratory dishes to study the impact on cell energetics. Finally, the team will study specific markers of Ak1 and Ak2 activity in brain tissue from individuals who had DLB  and cognitively unimpaired individuals.

Impact

The results may reveal how the brain’s support cells impact the formation of Lewy bodies in nerve cells. The findings may add to our understanding of neurodegenerative diseases characterized by abnormal protein clumps in the brain, including DLB, Parkinson’s disease, and Alzheimer’s.