Steven Estus, PhD
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JAD profile
Associate Editor
Term Expiration:
12/31/2024
Affiliation(s):
University of Kentucky
Areas of Interest:
Alzheimer's disease genetics, alternative splicing, microglia
Biography & Research:
I obtained my PhD in pharmacology and then worked on amyloid protein precursor processing with Steven Youkin. After a second post-doctoral stint with Gene Johnson focusing on the molecular basis for neuronal apoptosis, I was recruited to the Sanders-Brown Center on Aging at the University of Kentucky. Since then, I have served on many NIH study sections, the BrightFocus and ADDF review panels, and the Journal for Neuroscience and Molecular Neurodegeneration editorial boards.
In our laboratory, we seek to elucidate the mechanisms underlying the actions of genetic polymorphisms that modulate the risk of disease, especially Alzheimer’s disease (AD). Our goal is to translate these findings into novel approaches to prevent or treat human disease. We are primarily focused on AD genetics because genetic risk factors drive the majority of AD risk. Also, since genetic variants modulate AD risk, then by definition, drugs that act similarly will also modulate AD risk. Hence, we interpret the pathways identified by genetics as validated drug targets.
Our experimental approach begins by noting that high throughput genome wide association studies have identified a series of single nucleotide polymorphisms (SNP)s that are robustly associated with AD risk. Hence our goal is to perform molecular genetic studies to identify the mechanisms of action underlying these SNPs. The primary actions of these SNPs, or their co-inherited proxy SNPs, are to (i) alter amino acid sequence, (ii) alter gene expression or (iii) alter mRNA splicing. For each of the AD-associated SNPs, we are working through the process of determining the molecular impact of the SNP. For example, a CD33 SNP has been associated with AD risk. We found that this SNP acts through a co-inherited proxy SNP to modulate the splicing efficiency of the second exon in CD33. The allele that protects from AD risk reduces the inclusion of exon 2. The CD33 isoform lacking exon 2 is predicted to produce a non-functional CD33. Hence, our findings suggest that reducing CD33 function protects from AD risk. We are currently pursuing this hypothesis at multiple levels, including the study of CD33 inhibitors.
Overall, our work is facilitated by our association with the Sanders-Brown Center on Aging and its Alzheimer's Disease Center (ADC). Our ADC has been critical in providing hundreds of DNA samples from well-characterized AD and control individuals, which are necessary for genotyping polymorphisms, as well as autopsy-derived CSF and brain samples, which has allowed us to quantify the levels of the gene products and genetic variant proteins of interest in a rapid and human-disease relevant fashion. We have similar projects that focus upon other AD-related polymorphisms, as well as pilot studies to evaluate the actions of polymorphisms that modulate the risk of multiple sclerosis, migraine, and ALS.
In summary, the overall goal of our laboratory is to use human genetics to identify molecular mechanisms that modulate the risk of human disease, especially AD. These studies contribute to the fight against AD by identifying individuals at risk, identifying possible novel therapies, and tailoring therapy to responsive individuals.
