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New research reveals a mitochondrial gene that protects against dementia and other diseases of aging

Image source: www.gero.usc.edu

New research from USC has uncovered a previously unknown genetic risk factor for Alzheimer’s disease and related dementias. The study provides insights on how these conditions, and other diseases of aging, might one day be treated and prevented.

The research from the Cohen Lab at the USC Leonard Davis School of Gerontology sheds new light on the protective role of a naturally occurring mitochondrial peptide, known as humanin. Amounts of the peptide decrease with age, leading researchers to believe that humanin levels play an important function in the aging process and the onset of diseases linked to older age.

“Because of the beneficial effects of humanin, a decrease in circulating levels could lead to an increase in several different diseases of aging, particularly in dementia,” said senior author Pinchas Cohen, dean of the USC Leonard Davis School and one of three researchers to independently discover the existence of humanin 15 years ago.

The study, Humanin Prevents Age-Related Cognitive Decline in Mice and is Associated with Improved Cognitive Age in Humans, led by Kelvin Yen of the USC Leonard Davis School, appears online on Sept. 21 in the Nature-published journal Scientific Reports. Among the findings, the researchers discovered a significant difference between the circulating levels of humanin in African-Americans, who are more impacted by Alzheimer’s disease and other diseases of aging, as compared to Caucasians.

“We have now discovered a novel underlying biological factor that may be contributing to this health disparity,” said Yen, a research assistant professor of gerontology.

Because humanin is encoded within the mitochondrial genome, the research team examined the mitochondrial DNA for common genetic variations known as SNPs (pronounced snips) that could explain the differences between humanin levels. According to the paper, after sequencing the entire mitochondrial genome of all samples to determine if any SNPs correlated with humanin levels, they identified a genetic variation that was associated with a 14 percent decrease in circulating humanin levels.

This provides the first evidence that a variation in the sequence of a mitochondrial peptide is associated with a change in the level of peptides and the first conclusive demonstration that mitochondrial peptides are encoded in and regulated through mitochondrial DNA, Cohen said.

The team subsequently examined the effect of this SNP in a separate large cohort of participants from the Health and Retirement Study, a longitudinal study of approximately 20,000 individuals over the age of 50 in the United States, of which more than 12,500 individuals consented to DNA analysis. Using this data set, the researchers report finding that the unfavorable version of this SNP, associated with low levels of the humanin peptide, is also associated with accelerated cognitive aging, providing the first demonstration linking a humanin SNP in the mitochondria to cognitive decline in people.

The paper also shows that in mice, injections of humanin delay cognitive decline associated with aging, proposing a possible therapeutic role for humanin-related drugs. The mechanism through which humanin acts to mediate these effects involves suppression of inflammation systemically, as well as specifically in the brain.

News source: www.gero.usc.edu

Biparental Inheritance of Mitochondrial DNA in Humans

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Mitochondrial diseases could be treated with gene therapy

Image source: drugtargetreview.com

Researchers have developed a genome-editing tool for the potential treatment of mitochondrial diseases: serious and often fatal conditions which affect 1 in 5,000 people.

The researchers, led by the University of Cambridge, applied an experimental gene therapy treatment in mice and were able to successfully target and eliminate the damaged DNA in mitochondria which causes the devastating conditions.

Their results could provide a practical route to treating patients with these diseases and may provide a future alternative to mitochondrial replacement therapy, or ‘three-parent IVF’. This is the first time programmable genome engineering tools have been used inside a living animal, resulting in such significant modification of mitochondrial DNA.

Mitochondria are the powerhouses inside our cells, producing energy and carrying their own DNA. They are inherited from a person’s mother via the egg, but if they are damaged, it can result in a serious mitochondrial disease. For example, MELAS Syndrome is a severe multi-system disorder causing progressive loss of mental and movement abilities, which usually becomes apparent in early childhood.

There are typically about 1000 copies of mitochondrial DNA per cell, and the percentage of these that are damaged, or mutated, will determine whether a person will suffer from mitochondrial disease or not. Usually, more than 60% of the mitochondrial DNA molecules in a cell need to be mutated for the disease to emerge, and the more mutated mitochondrial DNA a person has, the more severe their disease will be. Conversely, if the percentage of mutated DNA can be reduced, the disease could potentially be treated.

Mitochondrial diseases are currently incurable, although a new IVF technique of mitochondrial transfer gives families affected by mitochondrial disease the chance of having healthy children – removing affected mitochondria from an egg or embryo and replacing them with healthy ones from a donor.

“Mitochondrial replacement therapy is a promising approach to prevent transmission of mitochondrial diseases, however, as the vast majority of mitochondrial diseases have no family history, this approach might not actually reduce the proportion of mitochondrial disease in the population,” said Dr Payam Gammage, a postdoctoral researcher in the MRC Mitochondrial Biology Unit, and the paper’s first author.

“One idea for treating these devastating diseases is to reduce the amount of mutated mitochondrial DNA by selectively destroying the mutated DNA, and allowing healthy DNA to take its place,” said Dr Michal Minczuk, also from the Medical Research Council (MRC) Mitochondrial Biology Unit, and the study’s senior author.

To test an experimental gene therapy treatment, which has so far only been tested in human cells grown in petri dishes in a lab, the researchers used a mouse model of mitochondrial disease that has the same mutation as some human patients.

The gene therapy treatment, known as the mitochondrially targeted zinc finger-nuclease, or mtZFN, recognises and then eliminates the mutant mitochondrial DNA, based on the DNA sequence differences between healthy and mutant mitochondrial DNA. As cells generally maintain a stable number of mitochondrial DNA copies, the mutated copies that are eliminated are replaced with healthy copies, leading to a decrease in the mitochondrial mutation burden that results in improved mitochondrial function.

The treatment was delivered into the bloodstream of the mouse using a modified virus, which is then mostly taken up by heart cells. The researchers found that the treatment specifically eliminates the mutated mitochondrial DNA, and resulted in measures of heart metabolism improving.

Following on from these results, the researchers hope to take this gene therapy approach through clinical trials, in the hope of producing an effective treatment for mitochondrial diseases.

This work was supported by the Medical Research Council and was performed in collaboration with Sangamo Therapeutics and the Max Planck Institute for Biology of Ageing in Cologne.

News source: www.drugtargetreview.com

Reference: Payam A. Gammage et al. ‘Genome editing in mitochondria corrects a pathogenic mtDNA mutation in vivo.’ Nature Medicine (2018). DOI: 10.1038/s41591-018-0165-9.