2024 Alzheimer's Association Research Grant (AARG)

Role of 3D chromatin in Alternative Isoform Choice in Health and Dementia

What are the different ways that cells make hallmark proteins of Alzheimer’s?

Valeriya Malysheva, Ph.D.
University of Antwerp
Wilrijk, Belgium

Background

One hallmark brain change associated with brain diseases is the accumulation of certain proteins in the brain that can contribute to memory impairment. While each disease is distinct, protein “clumps” are often seen in the brains of people with Alzheimer’s, Parkinson’s, and Lewy body dementia.

A major focus of Alzheimer’s research is on the genetic mechanisms that might contribute to protein accumulation in the brain. This includes the way cells turn genes “on” or “off” to make proteins. When a gene is turned “on” a cell’s machinery makes a type of genetic material called ribonucleic acid (RNA, also known as transcripts). A single gene may make several different transcripts. This variability is controlled by a complex network of other proteins (called transcription factors), and varying gene “start” and “stop” sites within the genetic code. More detailed analyses are required to understand how these factors come together to drive protein production in the brain during brain diseases.

Research Plan

Dr. Malysheva and team will analyze gene activity in individual brain cell samples donated by healthy people and people who had different stages of Alzheimer’s, Parkinson’s, or Lewy body dementia. Their goal is to understand how gene activity and protein production changes over the course of disease progression.

The researchers will employ a highly sensitive technique, developed by Dr. Malysheva, that can distinguish different transcripts produced by the same gene. Their analysis will include how the 3-dimensional structure of genetic material changes gene activity inside different kinds of brain cells. In a second part of the study, the researchers will incorporate their findings into several large datasets that use machine learning to understand complex gene control networks inside cells. One goal is to investigate how cells affected by brain disease use different gene “start” and “stop” sites to make transcripts that provide the instructions for making proteins.

In a final step, the researchers will use computer algorithms to “remove” certain transcription factors from the datasets. This will allow Dr. Malysheva to predict how gene activity would change if a given transcription factor was removed. This last step will provide the foundation for therapeutic approaches designed to target gene control networks during Alzheimer’s and other brain diseases.

Impact

This study represents the first large-scale analysis of specific genetic mechanisms that drive alternative protein production in certain types of dementia. Results from this study could identify disease stage-specific genetic mechanisms that contribute to protein accumulation across brain diseases. These mechanisms might be targeted therapeutically as a way to delay, or slow disease progression.