The Role of Epigenetics and Methylation Near the DMPK Gene in Causing Neurodegeneration in Myotonic Dystrophy Type 1
Abstract
We propose to identify the mechanisms that cause the neuromuscular disease, Myotonic dystrophy type 1 (DM1), a Fiscal Year 2018 Peer Reviewed Medical Research Program Topic Area. DM1 is the most common form of adult-onset muscular dystrophy. It is a genetic disease that occurs in ~1 in 8,000 individuals. The disease produces a range of symptoms, with the more severe forms having an earlier disease onset. Mildly affected patients typically show cataracts and muscle weakness with adult or late onset. More severely affected patient?s exhibit myotonia and a number of brain disorders including learning difficulties, memory impairment, executive dysfunction, sleep abnormalities, psychiatric disorders, and personality abnormalities. The most severe form, congenital DM1, has onset from birth and congenitally affected patients show a distinct phenotype with mental retardation, breathing difficulties, and cardiac arrhythmias. There is no treatment that slows the progression of DM1. The genetic mutation that causes DM1 is a large number of cytosine-thymine-guanine trinucleotide repeats (CTG) in the dystrophia myotonica protein kinase gene (DMPK). Patients can usually be identified with genetic tests to identify the number of CTG repeats in the DMPK. This is similar to a more well-known trinucleotide repeat disorder, Huntington?s disease. For years, the disease severity was thought to be directly related to the number of CTG repeats in DMPK, the more CTG repeats the more severe the disease and the earlier the onset. However, newer evidence suggests that this dogma may be inaccurate; other molecular factors may contribute to disease onset and severity. Studies have now indicated that changes in epigenetics may contribute to onset, progression, and severity of DM1. Epigenetics involves modifications in the DNA that can change gene expression without causing mutations or changes in the primary structure of the DNA itself. In the case of DM1, methylation of the DMPK is an epigenetic change that may contribute to the appearance of disease symptoms. In fact, it is known that the DMPK is methylated and methylation can affect the expression of this gene. What is not known is how methylation contributes to cellular dysfunction and disease progression. What is also not known is the role of epigenetics in neurodegeneration even though a major disability in DM1 is impaired brain function. Our studies propose to identify the mechanisms by which methylation of the DMPK cause neurodegeneration and disease severity. This is important in the outlook of developing more effective treatments of the disease because there is a growing effort to develop new medicines that target epigenetics and reduce DNA methylation to treat other neurodegenerative diseases. If we had ways to test those drugs for efficacy at an early preclinical stage for treating DM1, they could be rapidly transitioned to testing in DM1 patients in clinical trials. The first studies we propose are to develop new preclinical human cell-based models of DM1 that can be used to discover what causes neurodegeneration in DM1 and that can also be used to test novel therapeutics for efficacy in treating this disease. We will do this by using an innovative technology that can directly convert the fibroblasts of DM1 patients to neurons. The approach we will use is different from the one used by many investigators to generate induced pluripotent stem cells from patients. The approach we will use is an important new way to generate patient neurons because it retains the epigenetic status of the patient?s genome in the neurons. No other technology can do this. As a consequence, we can study the levels of methylation of the neurons from DM1 patients with different disease severity. We will combine this new way to generate neurons from different DM1 patients with an innovative technology to monitor the gradual degeneration of the neurons over extended periods of time, all
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 05, 2019
- Source ID
- W81XWH1910095
Entities
People
- Steven Finkbeiner
Organizations
- The J. David Gladstone Institutes
- United States Army