10 March 2017

Lemurs have proven the mitochondrial nature of dementia

Denis Strigun, Naked Science

American scientists have shown that chromosomal rearrangements of Alu repeats in the TOMM40 gene potentially allow predicting mitochondrial pathologies characteristic of the early stages of Alzheimer's disease. The article was published in the journal Alzheimer's & Dementia (Roses et al., A TOMM40 variable-length polymorphism predicts the age of late-onset Alzheimer's disease).

Alzheimer's disease, or senile dementia, is an age-related neurodegenerative disease that manifests itself in a gradual breakdown of mental functions and leads to death. According to According to the United Nations (UN), in 2006, more than 26 million cases of the disease were recorded in the world. Despite its prevalence, there are no ways to treat this form of dementia. Past work has revealed many candidate genes associated with the risk of Alzheimer's disease, but in the case of individual loci, their explanatory power does not exceed four percent.

The etiology of the disease also remains unclear. The dominant hypothesis is that links the development of Alzheimer's disease with the accumulation of neurofibrillary tangles and amyloid plaques in the brain that "glue" neurons and disrupt their work. The "amyloid" hypothesis is confirmed by many observations, but experimental drugs designed to destroy beta-amyloid "couplings" have repeatedly failed during human trials. So, in November 2016, solanezumab failed the third phase of clinical trials.

In 2004, specialists from the University of Virginia Health System proposed the "mitochondrial cascade hypothesis" as an alternative. The fact is that, unlike other cells, most neurons stop dividing after birth, which increases the risk of accumulation of "errors" in their mitochondria. According to this hypothesis, mitochondrial pathologies lead to energy starvation and death of nerve cells and, as a consequence, to neurodegenerative diseases.

Until recently, how mitochondria shrink with age was unknown. But in 2009, a group of American neurologists found a correlation between the risk of Alzheimer's disease, the translocase gene of the outer mitochondrial membrane 40 (TOMM40) and Alu repeats - mobile genetic elements whose chromosomal rearrangements (on introns 6 and 9 TOMM40) lead to a violation of adenine–inosine RNA editing and are associated with hereditary human diseases. In particular, the non-coding region of TOMM40, including Alu repeats, had different lengths.


Normal and truncated TOMM40 transcripts. The main changes in the secondary structure are highlighted in blue / Drawing from an article in Alzheimer's & Dementia

In a new paper, scientists from Duke University tested the number of mobile elements in 1,145 genes encoding mitochondrial proteins and in 8,973 random genes of the gray mouse lemur (Microcebus murinus) – like humans, this primate species can experience symptoms characteristic of Alzheimer's disease. After that, the indicator was compared with other lemur species (Lemuridae). The results showed that the number of Alu repeats in the TOMM40 gene of the gray mouse lemur was higher than in the rest of the family. According to the simulation, the excess of Alu repeats limited the expression of the gene, which led to the truncation of the amino acid sequence of its transcript. In this case, the 3’ end of the RNA molecule is 335 sequences long (at a norm of 361 sequences) coincided with the AluY repeat on intron 9.

It is noteworthy that multiple inserts of Alu repeats in genes encoding mitochondrial proteins have been associated with neurodegenerative diseases before. Thus, an excess of retrotransposons in the ABCD1 gene region was found in patients with adrenoleukodystrophy, and in the OPA1 gene – in patients with dominant optic nerve atrophy. According to the authors, this indicates that rearrangements in Alu repeats editing transcripts of mitochondrial genes are probably a common marker of pathologies of the central nervous system (CNS). In the future, the analysis of such mobile elements can help in the early diagnosis of Alzheimer's disease and its treatment.

In recent years, various groups of researchers have proposed promising methods of treating Alzheimer's disease. So, experiments have shown that it is possible to slow down the deterioration of memory in such patients by inhibiting nicotine receptors, and caffeine, fantasy reading and special video games are suitable for the prevention of senile dementia.

Portal "Eternal youth" http://vechnayamolodost.ru  10.03.2017

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