A Genetic Screen to Identify New Drug Targets for Alzheimer Disease

Huda Zoghbi, MD
Baylor College of Medicine (Houston, TX)

Co-Principal Investigators

Juan Botas, PhD
Baylor College of Medicine
Year Awarded:
Grant Duration:
July 1, 2016 to June 30, 2019
Alzheimer's Disease
Award Amount:
Grant Reference ID:
Award Type:
Award Region:
US Southern
Huda Zoghbi, MD

Genetic Screens to Identify Targets that Regulate Amyloid Precursor Protein (APP)


Alzheimer disease (AD) is characterized by the deposition of amyloid plaques and the accumulation of neurofibrillary tangles (eg, tau tangles), These AD pathologies are the, products of amyloid precursor protein (APP) processing and tau hyperphosphorylation, respectively. Several studies demonstrate that reduction of APP is therapeutically beneficial in AD mouse models. This evidence prompted us to hypothesize that modest reduction in the levels of APP proteins would delay the onset and retard progression of AD.  We plan to identify new therapeutic targets using an unbiased, high-throughput screen that employs two different assay systems in parallel (human neuronal cell lines and fruit flies expressing human APP).Our goal is to identify those proteins whose reduction results in lower levels of APP, and whether this reduction rescues neuronal degeneration in flies. 


The major goal of this project is to discover new therapeutic targets for Alzheimer disease (AD). We propose a research program centered on genes and genetic networks that control amyloid precursor protein (APP) levels using innovative screens of the “druggable” genome. In Aim 1, we will employ two different assay systems in parallel (human neuronal cell lines and Drosophila, eg, fruit-flies expressing human APP) to identify those proteins whose reduction results in lower APP levels. This type of screening paradigm is novel and we have found this approach fruitful in other disease models. One system will use shRNAs [short hairpin RNAs] targeting the druggable human genes to find those whose reduction lowers APP levels in reporter lines. In parallel, we will perform a loss-of-function screen targeting the homologues of the same genes in Drosophila, looking for modifiers of APP-induced neuronal dysfunction. In Aim 2, shared hits from these screens will be prioritized based on: (1) existing genomic and transcriptomic data from human AD patients, (2) pathway enrichment analysis, and (3) availability of known chemical inhibitors. We will confirm the top modifiers in cells and then assess available inhibitory compounds on endogenous APP levels in cells. The top confirmed hits will then be further validated in primary neuronal cultures from wild-type and APP mice. By the end of this project, we will have a set of optimal candidate therapeutic targets ready for genetic knock-down in the mouse brain, as well as for use with known small-molecule inhibitors for further preclinical drug development in mouse models of AD. Assembly of the results into established regulatory pathways, together with validation using known small molecules, should greatly improve our understanding of the regulation of APP protein levels and accelerate the discovery of new therapeutic leads for the treatment of AD.

About the Researcher

Dr. Huda Zoghbi earned her bachelor of science degree in biology from the American University of Beirut (Lebanon). She enrolled in medical school at the American University of Beirut, but due to the war in Lebanon, Dr. Zoghbi transferred to Meharry Medical College in Nashville, Tennessee, where she earned her medical degree. After residency and postdoctoral research training at Baylor College of Medicine (Houston), she joined the Baylor faculty in 1988. Dr. Zoghbi became an investigator with the Howard Hughes Medical Institute in 1996. In 2010, she became the founding Director of the Jan and Dan Duncan Neurological Research Institute. Dr. Zoghbi has made a series of seminal contributions to our understanding of inherited neurological disorders. Since identifying an expanded trinucleotide repeat as the cause of spinocerebellar ataxia type 1 (SCA1), in collaboration with Dr. Harry Orr, she has led the polyglutamine field in understanding the role of protein misfolding in pathogenesis and provided a molecular mechanism to show how the gain of function in ataxin1 involves enhanced function. More recently, her team and collaborators highlighted the importance of protein levels in this class of disorders and developed a strategy to uncover new druggable targets for SCA1 and other degenerative diseases, such as Alzheimer disease, that are driven by enhanced protein levels or activities.  Dr. Zoghbi also discovered that the sporadic disease Rett syndrome is caused by mutations in MECP2 [methyl CpG binding protein 2] and provided insight into the effect of MECP2 dysfunction on various neurons. Zoghbi’s studies of normal brain development have also, inevitably, led back to the clinic: her work on the Math1 gene has shed light on hearing, proprioception, neonatal breathing, and medulloblastoma.

Personal Story

I was enrolled in medical school at American University in Beirut when war erupted in Lebanon, in 1975. When I went home after my first year, fully intending to return to school in the fall, I learned that my younger brother had been hit by shrapnel. He wasn’t badly injured, but our parents decided to send me and my brothers to stay with relatives in the United States for the summer. The war escalated, I could not return home, and I transferred to Meharry Medical College in Nashville, Tennessee.

I was nearing the end of my training as a pediatric neurologist when I met a young patient who changed my life. The five-year-old girl had developed normally until she was 18-24 months old, but then she had regression and balance problems, constantly wrung her hands, and could not communicate. An encounter with a girl with a similar clinical picture, one week later, affirmed my interest in the disorder. Unable to offer the girls’ parents any answers, I set out to find some. I studied molecular genetics and dedicated my career to research.

Sixteen years later, my team at Baylor College of Medicine identified a gene that, when mutated, causes Rett syndrome, the enigmatic disease I first encountered in 1983. I later found that mutations in that gene, MECP2, can cause neurological problems beyond those typical of Rett syndrome, and showed that the protein it produces is critical for mature neurons to function in the brain.

As a Howard Hughes Medical Institute (HHMI) investigator since 1996, I now run a lab that studies neurodevelopment and neurodegeneration from several different angles. Many neurodegenerative diseases – including Parkinson, Alzheimer, and Huntington – are caused by the buildup of toxic proteins in the brain. My lab showed that the rare disease spinocerebellar ataxia (SCA1) is caused by the toxic protein ataxin-1. That research has had broad implications for the understanding of this class of diseases, and the role protein levels play in disease neurobiology.

Drugs that clear toxic proteins from the brain might improve symptoms in patients with such diseases. So with a Collaborative Innovation Award from HHMI, my lab and a team of scientists (Drs. Juan Botas and Thomas Westbrook of Baylor College of Medicine, and Dr. Harry Orr of University of Minnesota) with genetics and neurobiology expertise collaborated to explore an ambitious new approach to discovering targets for potential drugs. The strategy led us to a signaling pathway that, when blocked, prevents the buildup of ataxin-1 in nerve cells, fruit flies, and mice with SCA1 – a starting point for developing therapies.  This strategy has most recently proven to be applicable to other neurodegenerative disorders including Alzheimer and Parkinson disease.

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