Amyotrophic lateral sclerosis (ALS), perhaps more commonly known as Lou Gehrig’s disease, is a devastating neurological disease that ultimately leads to death. This disease eats away at nerve cells, causing death to the motor neurons in the brain and spinal cord, resulting in the loss of muscle function and eventual paralysis and respiratory failure.
ALS occurs in 2 main types: Sporadic and Familial. Sporadic ALS is the most common form, and it occurs in individuals in their late 50’s/early 60’s with no family history of the disease. According to ALS News Today, this type comprises about 90-95% of all ALS cases in the US. Familial ALS is the inherited version of the disease and is far rarer—only about 5-10% of all ALS cases in the US are familial, and symptoms typically begin to exhibit themselves around late 40’s early 50’s.
Currently, there are no cures or even any successful methods that slow this disease’s progression. According to a study out of Brooklyn College, however, epigenetics may help point future research in the right direction towards practical diagnostic tools and potential treatments.
In this study published in Translational Research, Dr. Mariana Torrente and her research team wanted to explore ALS from an epigenetic angle. “Epigenetic mechanisms are reversible. If there is an epigenetic problem, you can use a small molecule or peptide drug to counteract the effect and bring it back to normal,” said Torrente, highlighting the flexible treatment options that epigenetics may offer.
The team decided to assess the role that different epigenetic mechanisms play in the ALS. They focused their efforts on reviewing DNA methylation, miRNA, and most specifically, histone deacetylases.
DNA methylation is an epigenetic process that occurs when methyl groups are added to the cytosine, resulting in altered gene expression. Evaluation of post-mortem spinal cord samples from patients with sporadic ALS have been shown to exhibit irregular global DNA methylation patterns. This variability suggests that both over and under expression in genes related to inflammatory and immune response may be involved in ALS.
A MicroRNA (miRNA) is a small, non-coding RNA that pairs with mRNA and prohibits it to be transcribed appropriately with the correct proteins, resulting in its degradation and altered gene expression. Increased levels of miRNAs found in the spinal cord have been associated with altered immune response, difficulties in brain development, and cell death – all of which are consistent with other debilitating neurodegenerative diseases like Parkinson’s and Alzheimer’s. Dr. Torrente recommends that screening for miRNAs could be effective for early detection of ALS.
Histone deacetylases (HDACs) are post-translational histone modifications that remove acetyl groups from histones. Acetyl groups loosen chromatin, allowing for an increase in gene expression. However, when these acetyl groups are removed, chromatin becomes tighter and less accessible, which inhibits gene expression. HDACs have been a popular target for treatment in cancers and other inflammatory and neurodegenerative diseases, so Dr. Torrente believes they could be a valid target for ALS as well.
The team primarily examined histone deacetylases (HDACs) activity in patients with ALS, as well as in mice and yeast models. They found that humans and mice exhibited unbalanced levels of HDAC – specifically HDAC11, while HDAC2 was also altered in humans. In mouse models, partial deletion of HDAC6 activated the clumping of enzyme SOD1, which increased motor neuron loss. They also found low levels of SIRT1 in nerve cells, but high levels of it in the muscle cells, indicating that SIRT1 may be a prospective biomarker to look out for when detecting ALS.
Interestingly in the yeast models, the scientists found both decreased and increased levels of acetylation between the different models, implying that different combinations of histone modifications may lead to the development of ALS. Although further research is needed, Dr. Torrente and her team suggest that HDAC inhibitors may be useful in reversing nerve damage and improving motor function.
The findings included in this study possess valuable information and may lay the groundwork for finding cures for ALS and all other neurodegenerative diseases. Although only a few potential epigenetic areas are highlighted here, the scientists believe they have only scratched the surface in this area of research: “We expect discoveries to come in the next decade will take us beyond establishing the links between ALS and epigenetics and move towards elucidating the precise epigenetic mechanisms associated with disease processes and specific symptoms.”
Source: Torrente M.P, et al. (2018). Epigenetics in amyotrophic lateral sclerosis: a role for histone post-translational modifications in neurodegenerative disease . Translational Research, 204(1) 19-30.
Reference: Jose Marques Lopes, ALS News Today Studying Epigenetic Changes Could Lead to New ALS Treatments and Biomarkers, Researchers Suggest. ALS News Today-News. 29 April 2019. Web.