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2011 Grants - Munkasci
HDAC Inhibition: Treating Dementia Through Cholesterol Transport and CLU
Andrew Munkasci, Ph.D.
Columbia University Medical Center
New York, New York
2011 New Investigator Research Grant
Proteins called histones have been shown to regulate the expression of genes. Histones can be modified by a process called deacetylation, or the removal of a group of atoms called the acetyl group. Abnormal deacetylation can hinder the brain's ability to form memories, and enzymes, cutting proteins, called histone deacetylase (HDAC) inhibitors have been used as a treatment for Alzheimer's disease. However, scientists know little about the genetic mechanisms that underlie the therapeutic ability of HDAC inhibitors.
Andrew Munkasci, Ph.D., and colleagues have been studying the many genes that HDAC inhibitors may "turn off," or prevent from being processed into proteins. As part of this process, they have found that an HDAC inhibitor called suberoylanilide hydroxamic acid (SAHA) moderates the defective transportation of cholesterol within cells during Niemann-Pick type C disease. This neurological disorder is similar to Alzheimer's in that it involves accumulations of the protein fragment beta-amyloid. In fact, SAHA is one of several HDAC inhibitors used to treat memory deficits in Alzheimer's disease. Dr. Munkasci and colleagues hypothesize that SAHA's effectiveness as a memory drug stems from its ability to prevent beta-amyloid accumulations in the brain by maintaining proper transportation of brain cholesterol. SAHA's preventative activities, the researchers further argue, are achieved because the drug is able to restore to normal levels a gene called CLU, which produces a key protein involved in cholesterol regulation.
For this study, Dr. Munkasci's team will use cultured cells and autopsied human brain tissue to test its hypotheses. They expect to clarify how HDAC inhibitors may prevent dementia-related neurological damage. As part of this effort, they plan to identify which genes are involved in HDAC inhibition. Such research could lead to novel therapies for preventing or treating Alzheimer's disease.