Friday, May 3, 2024
5/3/2024
PROJECT SUMMARY/ABSTRACT (30 lines of text): Alzheimer’s disease, the most common form of dementia, is characterized by cognitive decline and impairment of behavioral and functional abilities. Approximate 5.8 million people in the United States are affected by Alzheimer’s disease (AD) and this number is anticipated to triple by 2050. While mutations in amyloid precursor protein (APP) and presenillin (PSEN1 and PSEN2) are known to cause familial early onset AD and the APOE4 variant is a well-known disease risk factor, the genetic contributions to the majority of late onset AD cases are not clear. Additionally, while the accumulation of Aß plaques and hyperphosphorylated tau are considered to be hallmark features of AD cases, Aß plaques and tau tangles do not fully explain the clinical features and heterogeneity found in AD patients. The identification of the C9orf72 GGGGCC hexanucleotide repeat expansion as the most common genetic cause of amyotrophic lateral sclerosis and frontotemporal dementia raises an intriguing question whether unidentified repeat expansion mutations contribute to other form of dementia including AD. Additionally, similarities in disease pathology are observed between AD and patients with repeat expansion disorders. These similarities include the accumulation of abnormal proteins, neuronal loss in affected brain regions, and the involvement of stress in worsening disease. While repetitive elements account for a large portion of the human genome, the detection repeat-expansion mutations, especially GC-rich repeat expansions, is challenging. To overcome the difficulties in identifying repeat expansion mutations, I have developed a novel dCas9-based repeat pull-down method (dCas9READ) that allows the isolation of repeat expansion mutations directly from the genomic DNA of individual patients. The objective of this proposal is to test the hypothesis that novel repeat expansion mutations contribute to late onset AD and their repeat containing RNA and RAN products are toxic and contribute to AD pathology. I am excited to report that in an initial screen, 17.5% of human AD autopsy cases tested were positive for RAN protein aggregates and RNA foci. In this grant, I will follow-up on these exciting preliminary data and test this hypothesis that novel repeat expansion mutations contribute to AD in the following specific aims: Aim 1) Will develop a novel dCas9-based technique for rapidly identifying repeat expansions. Aim 2) Will test the hypothesis that novel repeat expansions mutations are present at higher frequencies in late onset AD vs. control samples. Aim 3) Will test the hypothesis that novel repeat expansion mutations are toxic and contribute to AD pathology.
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