March 1, 2024

What is your risk for Parkinson’s disease? Your genes have a clue

This story is one of many that explore recent advances in the science of longevity and aging. Future articles in the series, including this one, will focus on the relationship between genetics and longevity; What genes are involved in aging and longevity? How are they involved? What are the therapeutic implications?

Aging is the biggest risk factor for Parkinson’s disease, a central nervous system disorder that causes uncontrollable movements and tremors. Although there are treatments available, there is currently no cure; We can help control the symptoms, but we don’t yet know how to combat the root causes. A new study may offer clues. Published in Molecular Psychiatry, research reveals a previously unidentified genetic mutation that provides a significant protective effect against Parkinson’s disease. Understanding the mutation could open new avenues for treatment and prevention.

The “forgotten” genome: mitochondrial DNA

When you think of genes, you probably think of DNA (deoxyribonucleic acid), the iconic molecule that carries our genetic code. Now, most DNA is housed in the nucleus of cells, which acts both as a safe room for our genetic material and as a kind of cellular control center. But a small portion of our DNA — about 1% — is housed elsewhere: the mitochondria. The name may sound familiar. These special organelles, many will remember, are “the powers of the cell”. In short, they help convert food energy into a cell-compatible format, enabling all kinds of important functions.

Mitochondrial DNA (mtDNA) is different from the ordinary DNA found in the nucleus. For one thing, the mitochondrial genome is circular rather than linear. It is also markedly smaller, reaching about 16,500 base pairs compared to the nearly 3.3 billion base pairs found in the nuclear genome. And where a large part of the nuclear DNA is “non-coding,” meaning it does not carry any proteins, the majority of the mitochondrial genome codes for proteins.

One of these mitochondrial proteins is called small humanin-like peptide 2 (SHLP2). It was first discovered in 2016 by the Pinchas Cohen Laboratory at the Leonard Davis School of USC. Follow-up experiments have shown that the microprotein helps protect against age-related diseases such as cancer. Furthermore, levels of the protein fluctuate in those suffering from Parkinson’s disease. After an initial spike, likely in an attempt to minimize damage caused by the disease, production slows quickly and eventually stagnates.

Genetic variant is extra protective

In this latest study, researchers at the Pinchas Cohen Laboratory went back to the protein to see if they could find something new. They pooled data from thousands of human study subjects collected as part of the Health and Retirement Study, Cardiovascular Health Study and Framingham Heart Study. They then examined the mitochondrial DNA of these individuals to check for any variation in the gene that produces the small humanin-like peptide 2.

In fact, they noted that about 1% of the population – mainly those of European descent – ​​carried a point mutation, which means a single change in one of the letters that make up the gene. On the surface, this may seem like a small difference, but it has serious implications: carriers of the variant are 50% less likely than the rest of the population to develop Parkinson’s disease.

The newly identified mutation alters the structure of the protein, making it more stable and leading to a higher rate of expression. This greater stability, in turn, helps the protein curb mitochondrial dysfunction, which is a key factor in the development of Parkinson’s disease.

As? The researchers noticed that a small humanin-like peptide 2 is present in the mitochondria of neurons, which are the fundamental cells of our central nervous system, responsible for sending and receiving sensory information throughout the body and brain. In particular, the microprotein binds to an enzyme called mitochondrial complex 1. This enzyme, which helps initiate cellular energy production, is a critical regulator of metabolism; Deficiencies in mitochondrial complex 1 have been linked to Parkinson’s disease, heart attacks and strokes.

The protective variant of small humanin-like peptide 2 binds to the enzyme especially tightly, slowing the decline in enzyme activity. Thus, those with the variant had improved mitochondrial complex 1 function and, by extension, fewer problems with mitochondrial dysfunction.

Apprenticeship

Parkinson’s disease is one of many age-related health conditions. As with others, it reduces the quality and expectancy of life. This new study by researchers at the University of Southern California helps highlight several important points. First, it identifies a previously unknown protective genetic variant found in mitochondrial DNA – carriers of which enjoy a twofold reduction in risk. In doing so, it serves as a powerful reminder that the mitochondrial genome, often forgotten or marginalized, can play an influential role in a range of age-associated diseases. Second, the study provides a detailed description of the molecular mechanism by which this mutation helps protect its carriers. In the future, we may be able to use this newfound information to develop effective therapeutic interventions that mimic the gene’s beneficial effects.

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