I have gathered many sources from the literature on Hutchinson-Gilford Progeria Syndrome (HGPS), my disease of choice for the bcm441 disease project. This disease is associated with premature aging. This literature I have collected is all fairly recent, majority of it coming from the last 15 years, as I have sources from 2003 to 2018. Most of what I have collected includes some important information that helps the field to somehow progress in its greater understanding of HGPS, and eventually led to some ideas for targets and drugs for treatment. I am going to organize my literature into four main categories.
The first main category involves understanding the genetic mutation and cause of the disease. This disease is caused by a non-inherited single nucleotide mutation at exon 11 of the LMNA gene, which normally encodes lamin A and C which are involved in nuclei shape. The mutation of LMNA leads to activation of splicing and truncation of prelamin A or progerin, a toxic precursor to lamin A. Progerin accumulation leads to HGPS and similar diseases along with their various bodily defects. Expression is also discussed in this category which discusses that lamin A is reduced in patients with the mutation. All of the information included in this section with refer to the underlying genetic causes and what lamin levels are typical of a HGPS patient. This information is the core of understanding majority of the further information within the other categories.
The second category involves specifically the inhibition of the farnesylation pathway. Farnesylation is known to control the toxic effects of progerin. Various inhibitors of farnesyltransferase and farnesyl pyrophosphate synthase were discovered in the literature and were found to inhibit farnesylation and caused various protein levels to normalize. These inhibitors of this specific pathway have the potential to treat certain HGPS symptoms. This pathway is extremely relevant in the disease and needed its own section due to its specific research.
The third category involves various different, yet specific targets for the disease, but in some way have the potential to control lamin A, progerin, their functions, or the whole aging process. For example, RNA-binding protein SRF1 can control the balance of lamins and there is a drug that can control SRF1 and therefore progerin expression. Another example involved the reduction of SUV39H1 levels allows DNA to repair and lifespan to increase. Others involve targeting the splice site, specific other genes expressed, or the telomere binding factors. All of these targets many have different effects, but it some way they have potential to be used to control the disease in different, yet specific ways.
The fourth category is a bit more broad in that it involves understanding the components that are causing the ceasing of cell division, DNA damage, and aging. For instance, nucleolar size and ribosomal biogenesis are factors caused by the disease that lead to the premature process of aging. Different aspects of defective DNA repair, such as longer G2 checkpoints, also contribute to cells ceasing to divide. Certain downstream targets of progerin are associated with senescence and aging, as well. All of these things help us to understand the different mechanisms in which the disease works to cause the phenotypical affects.
Of course all of these have certain overlapping points where it may be difficult to categorize them under one specific category, but I have done my best to put them into their most essential category.