According to a new study from the USC Leonard Davis School of Gerontology, a previously unidentified genetic mutation in a small protein provides significant protection against Parkinson's disease and offers a new direction to explore potential treatments. The variant, located in a mitochondrial microprotein called SHLP2, was highly protective against the disease.
Individuals with this mutation are half as likely to develop the disease as those who do not carry it. The variant form of the protein is relatively rare and is found primarily in people of European descent.
The results of research were published in the journal Molecular Psychiatry.
Parkinson's disease: new hope from the discovery of a genetic mutation
First discovered by Pinchas Cohen at the USC Leonard Davis School in 2016, SHLP2 is produced within the cell's mitochondria. Previous research from the Cohen Lab has established that SHLP2 is associated with protection from age-related diseases, including cancer, and that levels of the microprotein change in Parkinson's disease patients, increasing as the body attempts to fight off the disease, but they often fail to increase production as the disease progresses.
This latest discovery builds on the USC team's previous mitochondrial research and represents an advance at the intersection of longevity science, precision health and microprotein discovery.
“This study improves our understanding of why people might get Parkinson's and how we might develop new therapies for this devastating disease,” said Cohen, professor of gerontology, medicine and biological sciences and senior author of the study.
“Furthermore, since most research is conducted on well-established protein-coding genes in the nucleus, it highlights the importance of exploring mitochondrial-derived microproteins as a new approach to the prevention and treatment of diseases of aging.”
For this study, first author Su-Jeong Kim, research assistant professor of gerontology at the USC Leonard Davis School, conducted a series of experiments that took advantage of the lab-developed microprotein discovery pipeline that begins with an assay-based on big data to identify variants involved in the disease.
Thousands of human subjects from the Health & Retirement Study, Cardiovascular Health Study, and Framingham Heart Study were screened for the SHLP2 variant.
By comparing genetic variants in mitochondrial DNA in Parkinson's disease patients and controls, the researchers discovered a highly protective variant found in 1% of Europeans, which reduced the risk of the disease by twofold, to 50% of the average.
Subsequently, the researchers demonstrated that this natural variant causes a change in the amino acid sequence and protein structure of SHLP2.
The mutation, a single nucleotide polymorphism (SNP), or a single-letter change in the protein's genetic code, is essentially a “gain-of-function” variant associated with increased SHLP2 expression and also makes the microprotein more stable.
According to their findings, the SHLP2 variant has high stability compared to the more common type and provides greater protection against mitochondrial dysfunction.
The research team was able to use targeted mass spectrometry techniques to identify the presence of the tiny peptide in neurons and found that SHLP2 specifically binds to an enzyme in mitochondria called mitochondrial complex 1. This enzyme is essential for life and the decline in its function has been linked not only to Parkinson's disease but also to strokes and heart attacks.
The increased stability of the SHLP2 variant means that the microprotein binds more stably to mitochondrial complex 1, prevents the decline of the enzyme's activity and thus reduces mitochondrial dysfunction. According to the study, the benefits of the mutant form of SHLP2 were observed both in in vitro experiments on human tissue samples and in mouse models of Parkinson's disease.
“Our data highlight the biological effects of a particular genetic variant and the potential molecular mechanisms through which this mutation may reduce the risk of Parkinson's disease,” Kim said.
“These findings may guide the development of therapies and provide a roadmap for understanding other mutations found in mitochondrial microproteins.”
Until recently, our understanding of Parkinson's disease was quite limited, which was evident in the limited treatment options for managing this debilitating condition.
Our recent knowledge has focused mainly on the genetic factors responsible for familial cases, while the causal factors in the vast majority of patients have remained unknown.
In a further study, however, researchers at the University of Copenhagen have revealed new insights into the functioning of the brain in Parkinson's patients. Leading the discovery is Professor Shohreh Issazadeh-Navikas.
“For the first time, we can demonstrate that mitochondria, the producers of vital energy within brain cells, particularly neurons, are damaged, leading to breaks in mitochondrial DNA. This initiates and spreads the disease like wildfire through the brain,” says Issazadeh-Navikas and adds:
“Our findings establish that the spread of damaged genetic material, mitochondrial DNA, causes symptoms reminiscent of Parkinson's disease and its progression to dementia.”
Parkinson's disease is a chronic condition that affects the central nervous system, leading to symptoms such as difficulty walking, tremors, cognitive problems, and ultimately dementia.
The disease affects over 10 million people worldwide. While there is currently no cure, some medical treatments may offer relief from its symptoms.
Examining both human and mouse brains, the researchers found that damage to mitochondria in brain cells occurs and spreads when these cells have defects in antiviral response genes. They tried to understand why this damage occurred and how it contributed to the disease.
Their research led to an extraordinary revelation.
“Small fragments of DNA are actually released into the cell from the mitochondria. When these fragments of damaged DNA are lost, they become toxic to the cell, prompting nerve cells to expel this toxic mitochondrial DNA,” explains Issazadeh-Navikas.
“Given the interconnected nature of brain cells, these toxic fragments of DNA spread to nearby and distant cells, similar to an uncontrolled forest fire started by a random bonfire,” he adds.
Issazadeh-Navikas expects this study to mark the initial step toward better understanding the disease and developing future treatments, diagnosis, and measurement of treatment effectiveness for Parkinson's disease.
He also expressed hope that “detection of damaged mitochondrial DNA could serve as an early biomarker for disease development.”
Biomarkers are objective indicators of specific medical conditions observed in patients. While some biomarkers are common, such as blood pressure, body temperature, and body mass index, others provide information about particular diseases, such as genetic mutations in cancer or blood sugar levels for diabetes. The identification of a biomarker for Parkinson's disease holds significant promise for improving future treatments.
It may be possible that mitochondrial DNA damage in brain cells spreads from the brain into the blood. This would make it possible to take a small sample of a patient's blood for early diagnosis or to establish a favorable response to future treatments.”
Issazadeh-Navikas also envisions the possibility of detecting damaged mitochondrial DNA in the bloodstream, making it possible to diagnose disease or evaluate responses to treatment through a simple blood test.
The researchers' next endeavor is to study how mitochondrial DNA damage can serve as predictive markers for different stages and progression of the disease. “Additionally, we are dedicated to exploring potential therapeutic strategies aimed at restoring normal mitochondrial function to correct mitochondrial dysfunction implicated in disease.”
According to the Niguarda hospital, Parkinson's disease in Italy: “Today in Italy there are approximately 300,000 people with Parkinson's disease, and unfortunately this number is destined to increase. In the next 15 years it is estimated that there will be 6,000 new patients per year, half of whom are still of working age.
The most frequent risk factors include advanced age, family history, male sex, ethnicity (the most affected are Caucasians), various environmental factors, head trauma and mood disorders such as depression. While among the protective ones, physical activity is the most important, followed by work activity.
Research against this disease continues and neurologists continue to work intensely on new techniques that allow a diagnosis as early as possible, even pre-clinical, i.e. before the appearance of motor symptoms.
“For the purposes of an as early diagnosis – states the Director of the Neurology and Stroke Unit – it is very important that patients report to their specialist all those symptoms attributable to Parkinson's disease such as olfactory deficit, depression, pain in the large joints and behavioral disorders during sleep.
In fact, these are non-motor symptoms that can help identify individuals at risk of developing the disease 10-12 years in advance. In this way, symptomatic or neuroprotective treatment could be started in the pre-motor phase of the disease and it would be possible to change the course of the disease, slowing down its progression.”
The disease mainly appears around the age of 60, but in 10% of cases the onset can occur before the age of 40. “Typical symptoms are bradykinesia, i.e. difficulty and slowness in movements, tremor and rigidity – explains the specialist – . Often, in the advanced stage of the disease, it is accompanied by other non-motor disorders such as: musculoskeletal pain, constipation, sexual dysfunction, excess salivation (drooling) and decreased tone of voice.
Again: difficulty swallowing, insomnia, daytime drowsiness, depression, anxiety, memory loss, difficulty reasoning, planning and understanding. However, some of these non-motor symptoms can even anticipate the onset of the pathology by a long time.”
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