Epigenetics and Amyotrophic Lateral Sclerosis (ALS)

The ALS "Ice Bucket Challenge" social phenomenon is still going strong, have you taken the challenge? In such a hot summer, buckets of ice water pouring numerous celebrities all over the world is a really happy scene, however, do not forget, this activity is originally designed to arouse people’s attention to ALS.

Amyotrophic lateral sclerosis (Als) is a lethal degenerative disorder of motoneurons, which progresses to paralysis of almost all skeletal muscles. ALS is an orphan disease, with 1 to 2 per 100,000 new cases and a total of about 5 per 100,000 total cases each year, and death from respiratory paralysis is typically within 5 years.

Riluzole is the only FDA-approved drug that has been found to improve survival of ALS patients, while other treatments for ALS only relieve symptoms and improve the quality of life for patients.

About 90% of all ALS cases occurs apparently at random with no clearly associated risk factors, and about 10% are inherited. A significant number of patients suffering from ALS carry an expanded noncoding hexanucleotide repeat in the C9orf72 gene, referred to as c9FTD/ALS. This mutation may alter epigenetic mechanisms and consequently lead to decreased gene expression, while also leading to toxic RNA gain-of-function.

According to the previous study results, four mechanistic models of C9orf72-mediated ALS have been proposed. Haploinsufficiency is suggested by the finding of reduced levels of C9orf72 transcripts in ALS brains; the transcribed expansion forms nuclear RNA foci; the hexanucleotide repeat may promiscuously bind and sequester transcription factors; neurotoxicity of C9orf72 expansions is a form of illegitimate protein translation termed repeat-associated, non-ATG (RAN) translation.

Recent research on ALS has generally focused on pathological processes affecting the cell body, but it is clear that critical events in ALS pathogenesis implicate the neuronal periphery. For example, early peripheral denervation happens before ventral nerve root or cell body degeneration. Similarly, mutant-SOD1 mice also demonstrate presymptomatic muscle denervation and terminal axonal degeneration before anterior horn cell loss.

In addition, some experiments are carried out on epigenetic studies that characterize changes in gene expression and cellular function that are not inherited. For example, histones H3 and H4 undergo trimethylation at lysines 9 (H3K9), 27 (H3K27), 79 (H3K79), and 20 (H4K20) in all pathogenic repeat carrier brain samples of ALS model. Similarly, about 40% of c9ALS cases show hypermethylation of the CpG island located at the 5' end of the repeat expansion in blood, frontal cortex, and spinal cord.

Since the importance of epigenetic regulation in ALS, epigenetic related enzymes may be potential targets for the treatment of ALS.

Numerologist Warda is hooked on OG-L002 fishing, collecting. And lastly her encouragement comes from socializing along with her companions.