Parkinson’s disease is associated with mitochondrial dysfunction. Mitochondria are the organelles responsible, among other functions, for supplying energy to cells. Previous studies have shown that patients with Parkinson’s disease have mitochondrial DNA with defects in their cerebrospinal fluid, suggesting impaired mitochondrial function. However, it has remained unclear whether this dysfunction is a consequence of Parkinson’s disease or whether it occurs beforehand and contributes to its development.
To address this question, a team led by Ramón Trullas, Research Professor at the Spanish National Research Council (CSIC) at the Institute for Biomedical Research of Barcelona (IIBB-CSIC), and Alex Iranzo, from the Neurology Department of Hospital Clínic Barcelona, the University of Barcelona, and head of the Clinical Neurophysiology research group at IDIBAPS, conducted a new study. Both researchers are affiliated with the CIBER Network for Neurodegenerative Diseases (CIBERNED).
The study, published in eBioMedicine, part of The Lancet group, and largely funded by the Michael J. Fox Foundation (USA), focused on a cohort of patients with isolated REM sleep behavior disorder (iRBD). This condition affects deep sleep and is characterized by a lack of normal muscle relaxation, leading to sudden and sometimes violent movements of the limbs and trunk that may be associated with vivid or aggressive dreams.
Many patients with this disorder go on to develop Parkinson’s disease or dementia with Lewy bodies years later, which is why iRBD is considered an early stage of these disorders. Both conditions are characterized by the accumulation of abnormal protein deposits in the brain known as Lewy bodies, which are associated with neuronal death.
In collaboration with the Sleep Disorders Unit at Hospital Clínic Barcelona, the researchers analyzed samples from 71 individuals. Of these, 34 were diagnosed with REM sleep behavior disorder and later developed Parkinson’s disease or dementia with Lewy bodies; 17 had the same sleep disorder but remained disease-free; and 20 served as healthy controls without REM sleep behavior disorder or parkinsonism.
“We found that patients with REM sleep behavior disorder have higher levels of mitochondrial DNA carrying deletions compared with the control group,” explains Ramón Trullas, CSIC Research Professor and leader of the CIBERNED Molecular Mechanisms of Neurodegeneration group.
Unlike most cells in the body, neurons depend heavily on the energy provided by mitochondria for their long-term survival. Mitochondria contain their own DNA, which is essential for their proper function. The presence of circulating mitochondrial DNA with deletions suggests that mitochondria may be unable to generate sufficient energy to maintain neuronal activity and survival over time.
Margalida Puigròs, researcher at IIBB-CSIC and first author of the study, explains that “patients with REM sleep behavior disorder, both those who later developed Parkinson’s disease and those who did not, showed higher levels of circulating mitochondrial DNA with deletions—that is, mitochondrial DNA that has lost fragments of genetic material—in their cerebrospinal fluid compared with the control group.”
However, the most significant finding, she adds, “is that the amount of mitochondrial DNA carrying deletions is related to the time it takes for patients with REM sleep behavior disorder to develop the clinical symptoms of Parkinson’s disease.” In other words, the greater the number of deletions, the sooner the disease is likely to appear. This suggests that mitochondrial DNA dysfunction is a primary molecular mechanism in the pathophysiological cascade that precedes the full motor and cognitive manifestations of Parkinson’s disease.
Study of reference:
Mitochondrial DNA deletions in the cerebrospinal fluid of patients with idiopathic REM sleep behaviour disorder. Margalida Puigròs, Anna Calderon, Daniel Martín-Ruiz, Mònica Serradell, Manel Fernández, Amaia Muñoz-Lopetegi, Gerard Mayà, Joan Santamaria, Carles Gaig, Anna Colell, Eduard Tolosa, Alex Iranzo and Ramon Trullas. eBioMedicine. 2024;102: 105065 https://doi.org/10.1016/j.ebiom.2024.105065
