Somatic Gene Recombination of MAPT in Single Cells from Frontotemporal Lobar Dementia (FTLD) Brains with Tau Pathology
Abstract
Frontotemporal degeneration (FTLD) produces dementia and destruction of brain cells, referred to as neurodegeneration. It is the second most common neurodegenerative disorder for people under 65, and although certain gene mutations can cause rare, familial forms, 60%-85% of cases are considered sporadic (i.e., not inherited). Severe FTLD can progress to amyotrophic lateral sclerosis (ALS: Lou Gehrig’s disease), and the two diseases are thought to be closely related. As with Alzheimer’s disease (AD), which can sometimes occur at the same time as FTLD, there are no cures or disease-modifying therapies available for FTLD and it is not well understood. In order to find effective therapies for FTLD, we must learn much more about the roles that genes play. Our lab recently discovered a new kind of genetic mechanism that may have very broad relevance to FTLD: Somatic Gene Recombination (SGR). SGR causes genomic copy number increases (more than two) of individual genes, where new copies contain sequence alterations of various sizes (from a single base pair to full exon deletion). Importantly, these changes can differ from cell to cell, creating a genomic mosaic. We hypothesize that when SGR affects some known (and likely unknown) disease-linked genes, neuronal degeneration and disease can result. We have already proven a role for SGR in AD, via mutations in the Amyloid Precursor Protein gene (APP). APP variations were more prevalent in neurons from sporadic AD brains and contained single nucleotide variations that were previously identified in rare, familial AD brains. Here we hypothesize that SGR also operates in FTLD brains to produce gene variants for tau, involving its gene called microtubule associated protein tau (MAPT), analogous to APP in AD, to influence disease. Compelling preliminary data support SGR acting on MAPT, and we will pursue the proposal through three aims beginning first with an in-depth exploration of MAPT variant sequence diversity using our published sequencing and visualization techniques. Second, we will use both targeted and unbiased DNA and RNA sequencing methods to assess all genes for mosaic genomic variants produced by SGR that could affect FTLD. Lastly, we will use a series of human cell culture experiments designed to identify the functional consequences of variant proteins and their potential impact on cell survival, pathology, neurodegeneration, and disease progression within the brain. This study will address primarily two of the PRMRP’s Areas of Encouragement: (1) Basic research to establish research tools for disease pathology … and/or genetic syndromes; and (2) Research to identify risk factors (e.g., gene networks). A third area, “Research to understand the neurological basis of deficits in social cognition and emotional regulation,” is also relevant through the examination of three common FTLD subtypes: corticobasal degeneration, progressive supranuclear palsy, and Pick’s disease. Successful pursuit of this proposal will have significant impact for military personnel as well as civilian populations through further understanding the genetic mechanisms underlying FTLD. SGR is dependent on a class of enzymes called reverse transcriptases (RTs), which are also used by deadly viruses such as HIV. Inhibiting these enzymes may reduce the neurodegeneration in FTLD (and possibly other neurodegenerative conditions). Notably, antiviral therapies that inhibit RTs were approved by the FDA decades ago for treatment of HIV and are generally safe and widely available. Proving the role of RT-dependent SGR in neurodegeneration may therefore identify real-world therapeutic options for these devastating diseases.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110642
Entities
People
- Jerold Chun
Organizations
- Sanford Burnham Prebys Medical Discovery Institute
- United States Army