The Huntington's disease (HD) community has recently experienced setbacks, but a new research report may rekindle hope, it comes from an unexpected source: vitamin thiamine (B1), with the help of biotin (B7) . Researchers from several institutions in Spain and UCLA wrote in "Science Translational Medicine", "These results collectively indicate a lack of thiamine in the HD brain and suggest that HD patients may benefit from thiamine and/or Biotin supplement therapy."

Health care providers may recommend certain supplements for people with HD based on blood deficiencies (vitamin C, B12, E) or general health conditions. But the new discovery is different. The researchers did not set out to detect vitamin deficiencies, but explored the transmission of information in the cells of the HD brain, which led them to the biochemical barrier that revealed the thiamine/biotin connection.

In HD, the extra copy of the DNA triplet in the gene encoding the huntingtin protein (called Htt) disrupts the striatum of the brain, leading to characteristic uncontrollable movement and emotional performance. This effect comes from both the repetitions in the mRNA transcribed from the amplified gene and the extra copy of what the mRNA indicates to the cell: the amino acid glutamine. The long glutamine string called "polyQ" is common in a variety of brain diseases, including spinocerebellar ataxia and spinal bulbar muscular atrophy. (Q is the abbreviation for glutamine.)

Researchers look for genes, when mutations or abnormal expressions, will affect the mRNA and polyQ aberrations in the Htt gene behind HD. This led to a class of genes called CPEB, used for "cytoplasmic polyA element binding proteins."

Drosophila experiments show that CPEB controls a part of Htt mRNA, called poly A tail. The tail is an extension of the RNA base adenine (A) at the beginning, which stabilizes the mRNA, helps it exit from the nucleus and protects it from chewing by enzymes. Almost all mRNAs have poly A tails. The second piece of evidence related to the CPEB gene is that one of the genes controls the amount of other proteins in the HD brain.

The researchers evaluated the levels of four CPEB mRNAs (aka transcripts) in striatal slices of people who died of HD and control brains. They found that the level of CPEB1 in the HD brain was three times the normal level and half the normal level.

Next, the findings in the two mouse models echoed human brain detection. R 6/1 mice have the first coding part of the human Htt gene and exhibit the same CPEB perturbation. The second mouse model corresponds to "pre-presenting" people who have mutations but have not yet shown symptoms-only show a reduction in CPEB4. Perhaps the rise of CPEB1 did not occur because these mice did not live long enough to show symptoms—in rodents, this is the ability to stay upright on a moving tube called a rotating rod. These findings imply that CPEB4 levels fell before CPEB1 levels tripled.

When the researchers looked at the genes that CPEB mRNA controls its mRNA, they found three genes with extended polyA tails-and the expression of these three genes has also been altered in Alzheimer’s and Parkinson’s disease . But it is the mRNA of one gene that has a shorter polyA tail that unexpectedly brings vitamins into the picture: SLC19A3.

It is already known that the mutation in SLC19A3 causes a brain disease that can be treated with biotin and thiamine! Biotin-thiamine responsive basal ganglia disease (BTBGD) changes the protein that transports thiamine into the cell. This condition can cause drowsiness, irritability, tremors, cramps and uncontrollable movements, similar to HD. BTBGD results from a direct mutation of the thiamine transporter, and HD changes the expression of the gene encoding the transporter (the rate of transcription into mRNA).

Adding high doses of biotin to the diet of BTBGD patients can accelerate the transcription of SLC19A3, thereby increasing the level of protein that escorts thiamine into the cell. But the deficiency of thiamine is in the cerebrospinal fluid, not in the blood-which may explain why the blood thiamine levels in HD patients are normal.

The vitamin connection inspired further experiments. Striatal and cortical sections from the brains of deceased HD patients showed lower levels of thiamine transporters. The thiamine in the cerebrospinal fluid decreased, but the thiamine in the blood decreased, consistent with BTBGD.

More convincingly, from 3 weeks of age, HD mice given high doses of biotin and thiamine in water no longer fell from the rotating rod. The brains of mice that were given vitamins before manifestation had no problem.

On the face of it, the connection between vitamins and brain diseases that have evaded all treatment attempts for decades is good news. Taking vitamin tablets is cheap, safe and easy, and vitamins are distributed throughout the central nervous system. In addition, high doses of these two vitamins are known to treat similar diseases. Although people who appear beforehand and those who already have signs and symptoms of HD will definitely go to pharmacies to buy vitamins, the researchers urge caution.

"The doses of these vitamins that lead to the improvement of the HD-like phenotype in the mouse model are much higher than their recommended daily intake. In addition, it is important to emphasize that for the highest evaluated dose, we have observed toxicity in HD mice Signs. This led us to reduce the dose given to mice to the extent that there are no obvious side effects and have measurable positive results for HD-like phenotypes,” said Dr. José J. Lucas, corresponding author and research professor at the Center for Molecular Biology. Severo Ochoa is in Madrid, in an email.

Therefore, researchers are conducting open-label pilot clinical trials on a limited number of HD patients to "analyze whether the high doses of thiamine and biotin required for the therapeutic effects observed in mice are safe and resistant to Huntington’s disease patients. Accept." If everything looks good, a larger experiment will follow. At the same time, "it is important that patients do not take thiamine and biotin supplements without the advice of a neurologist," Lucas warned.

Until vitamin supplements are officially approved to slow, treat or delay the onset of HD, family communities with this disease are once again, and probably more hopeful than ever. This is priceless.

Thanks to Jane Mervar and Jonathan Monkemeyer for their help with this article.

Ricki Lewis has a PhD in genetics and is a scientific writer and author of several books on human genetics. She is an adjunct professor at the Alden March Institute of Bioethics at the Albany School of Medicine. Follow her on her website or Twitter @rickilewis

A version of this article was originally published on PLOS and republished here with permission. PLOS can be found on Twitter @PLOS

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