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Oliver Bandmann, MD, PhD Sheffield, South Yor United Kingdom | ||
| Mitofusin Ubiquitination as a Biomarker to Stratify Parkinson's Disease Patients UCL Ps65-ub (?)를 WBC 에서 보는 듯 | https://www.michaeljfox.org/grant/... parkinsons-disease patients |
Study Rationale: Some forms of early-onset Parkinson's disease are caused by dysfunction in the recycling of mitochondria, which are the powerhouses of our cells. Damaged mitochondria to be recycled are marked with a small protein named ubiquitin. This process does not happen in some early-onset patients, and the damaged mitochondria build up and cause the cell to die. Hypothesis: Our hypothesis is that the absence of the ubiquitin marking of damaged mitochondria in white blood cells can be used to identify patients with faulty mitochondrial recycling. Study Design: This current study aims to test the detection of ubiquitin marking of damaged mitochondria in white blood cells from healthy people and early-onset patients with a known mitochondrial recycling fault to ascertain the reliability of the assay. Blood samples will be collected from early-onset Parkinson's patients and people without the disease. White blood cells will be isolated and treated with a toxin that damages their mitochondria. We will then determine if the damaged mitochondria are marked for recycling with ubiquitin. In white blood cells from patients with a fault in mitochondrial recycling, the mitochondria will not be marked with ubiquitin. Impact on Diagnosis/Treatment of Parkinson's Disease: If we can detect the absence of ubiquitin marking of damaged mitochondria, we could identify patients with this mitochondrial dysfunction. These people could potentially test drugs designed to stimulate the recycling of damaged mitochondria, as they would be the most likely to benefit. Next Steps for Development: In future studies, we plan to test early-onset Parkinson's patients with an unknown disease cause to determine if they have a fault in the recycling of mitochondria. |
| N-formyl Peptides (NFP) as Novel Biomarkers for Parkinson's Disease University of the Highlands and Islands | https://www.michaeljfox.org/grant/... n-formyl-peptides-novel-biomarkers-parkinsons-disease |
Study Rationale: Mitochondria — the powerhouses of the cell — have their own DNA that contains the instructions to make thirteen proteins. Fragments of these proteins, known as N-formyl peptides can escape from the cell when mitochondria are damaged. The immune system perceives N-formyl peptides as dangerous and responds with inflammation, which ultimately leads to tissue injury. This process may play a role in the onset and progression of Parkinson's disease (PD).
This study will explore whether mitochondrial N-formyl peptides can be used as biomarkers — objective measures of disease — for early detection of Parkinson's. Study Design: The peptides will be measured in blood samples donated by people newly diagnosed with PD. Subsequent analyses of cerebrospinal fluid — — and brain samples will show whether the peptides come from the site of tissue injury. We will also search for correlation between the levels of N-formyl peptides in each of the sample types and the progression and severity of the disease. Impact on Diagnosis/Treatment of Parkinson's Disease: This study can potentially produce methods of early diagnosis and accurate prediction of disease progression. This will be critical to the development of effective therapies that require diagnosis before the onset of symptoms. Next Steps for Development: A better understanding of N-formyl peptides will provide the basis of a sensitive and specific test for PD that could be included into diagnostic programs in the future. This will also support further search for a cure for Parkinson's disease. |
| Studying Changes in Phosphatidylethanolamine as a New Marker of Parkinson's Disease | https://www.michaeljfox.org/grant/studying-changes-phosphatidylethanolamine-new-marker-parkinsons-disease |
Study Rationale: While most cases of Parkinson's disease (PD) have no known cause, some are caused by changes (mutations) in genes such as SNCA, which regulates the production of a protein called alpha-syn. Alpha-syn is a sticky protein that clumps in the brains of people with PD. In our recent work, we have been focusing on identifying the exact location of alpha-syn inside the cell. One such location is the mitochondria, powerhouses of the cell. Mitochondria attached to endoplasmic reticulum — a network of tiny tubes inside the cell — are known as mitochondria-associated endoplasmic reticulum membranes (MAM). MAM regulates several important cellular functions, one of which is the production and breakdown of molecules called phospholipids. Cf) {Calzada, 2019 #1277}
We have previously observed changes in phospholipids in pre-clinical models with Parkinson's features. We hypothesize that changes in mitochondria seen in PD can be due, at least in part, to changes in phospholipids, specifically, due to reduced levels of phospholipid phosphatidylethanolamine (PtdEtn). Study Design: We will evaluate the levels, production and breakdown of PtdEtn in blood samples collected at Columbia University Medical Center from people with Parkinson's disease and healthy people. Impact on Diagnosis/Treatment of Parkinson's Disease: The goal of this project is to study PtdEtn as a biomarker — objective measure of disease — to diagnose and monitor PD progression. Next Steps for Development: Our findings could guide high-throughput screening of drugs that can reverse PD-associated changes in the phospholipid pathway and in the mitochondria. |
| pS65-Ub as a Biomarker for Parkinson's Disease Mayo Clinic Wolfdieter Springer | https://www.michaeljfox.org/grant/ps65-ub-biomarker-parkinsons-disease |
Study Rationale: The PINK1 and parkin proteins jointly ensure quality control of mitochondria, the cell's powerhouse. Together they modify damaged mitochondria with phosphorylated ubiquitin (pS65-Ub), which appears to label the mitochondria for degradation. In some genetic forms of Parkinson's, PINK1 and parkin activity is lost, and mitochondrial dysfunction is more frequent in the broader Parkinson's population. Hypothesis: Given that pS65-Ub is a quantitative marker of mitochondrial damage, we hypothesize that pS65-Ub might be useful as a novel biomarker for Parkinson's disease. Study Design: In this proof-of-concept study, we aim to develop and optimize antibody-based assays to reliably quantify pS65-Ub from cells and different patient samples. We will determine the best assay conditions and antibody combinations, and assess their suitability as biomarkers for Parkinson's disease. Impact on Diagnosis/Treatment of Parkinson's Disease: Currently there are no biomarkers available for Parkinson's disease. However, these would be extremely valuable to diagnose and stratify patients as well as to the future development of therapies. Next Steps for Development: Upon successful development and optimization of the pS65-Ub assays and exploration of diverse patient specimens (cells, blood, cerebrospinal fluid) with limited sample numbers, next steps will include expansion to larger sample sizes of the respective specimens to establish pS65-Ub as a biomarker for Parkinson's. |
| Searching for Signs of Mitochondrial Breakdown in People with Parkinson's Disease with Unknown Cause Van Andel Institute Clinical Research, Catherine | https://www.michaeljfox.org/grant/searching-signs-mitochondrial-breakdown-people-parkinsons-disease-unknown-cause |
Study Rationale: Some inherited forms of Parkinson's disease (PD) are caused by mutations (genetic changes) that lead to the breakdown of mitochondria, cell's energy generators. In some sporadic PD — disease that is not inherited — mitochondrial breakdown might still be an underlying cause. Little is known about these cases because mutations have been the focus of research so far. Also, properly identifying the cause of sporadic PD has not been possible. We aim to identify people with Parkinson's who do not have a known mutation affecting mitochondria but have dysfunctional mitochondria nevertheless. This population is more likely to benefit from therapies targeting mitochondria. Hypothesis: We hypothesize that signs (markers) of mitochondrial breakdown present in some inherited forms of PD will also be present in a sub-group of people with sporadic PD. We hypothesize that the properties — mass and length — of mitochondrial DNA is a stable, robust and informative marker of mitochondrial breakdown. We will use appropriate controls for the normal variation in mitochondrial mass and length between individuals. Study Design: We will collect a small amount of blood from at least 50 people with sporadic PD, 50 healthy people and at least 15 people with inherited PD who have mutations in genes that regulate the production of mitochondria-related proteins. We will extract mitochondrial and nuclear DNA from a fraction of blood cells called mononuclear cells to look for similarities between groups of study participants. We can also store these samples and use them again to confirm or modify our findings. Impact on Diagnosis/Treatment of Parkinson's disease: This data will allow us to identify people with sporadic Parkinson's possibly caused by underlying mitochondrial breakdown. This will help clinicians to better organize trials of treatments targeting mitochondrial health. This data will also inform researchers of the contribution of mitochondrial breakdown to the overall cause of sporadic PD, allowing them to conduct a more focused search for new or improved therapeutic targets. Next Steps for Development: If our study is successful, sub-groups of people with sporadic Parkinson's could be invited to participate in clinical trials where approved compounds already known to improve mitochondrial health could be used, for example, certain antioxidants or compounds promoting mitochondrial renewal. Furthermore, the protocol for assessing mitochondrial breakdown could be used in larger patient cohorts and in cohorts at other clinics. In this case, mitochondrial breakdown would play a role of a standardized biomarker, i.e., an objective measure of disease. Finally, the identification of people with sporadic PD with likely mitochondrial breakdown via blood sample analysis could allow researchers to perform more in-depth studies using other techniques and/or cell types. |
| Changes in Mitochondrial DNA as Diagnostic and Prognostic Markers of Parkinson's Disease Cyprus Institute of Neurology and Genetics Zambacolaou, Catherine | https://www.michaeljfox.org/grant/changes-mitochondrial-dna-diagnostic-and-prognostic-markers-parkinsons-disease |
Study Rationale: Biomarkers, or objective measures, of Parkinson's disease (PD) could help identify individuals at risk of PD and predict disease progression. According to recent studies, changes in DNA, such as hydroxymethylation — the attachment of chemical hydroxymethyl — can serve as PD biomarkers. It is also known that DNA changes in mitochondria — powerhouses of the cells — can affect the risk of Parkinson's and other diseases. Hypothesis: In this study, we aim to identify PD biomarkers in mitochondria. These will represent biological changes in mitochondrial DNA (mtDNA), miniature DNA inside mitochondria. These changes could aid in diagnosis and prognosis by serving as a signal of disease or informing about disease progression, respectively. In addition, we will investigate whether diagnostic or prognostic biomarkers of Parkinson's are influenced by the environment. Study Design: The study will compare mtDNA of 180 people with PD with that of 360 healthy volunteers. The attachment of chemical methyl to mtDNA (methylation) will be evaluated in both groups of participants, and differences in methylation between the groups will be identified. We will also investigate whether these differences in methylation change as the disease progresses. This investigation will involve two small subgroups of participants: 10 people with the fastest and 10 people with the slowest disease progression. Impact on Diagnosis/Treatment of Parkinson's disease: Firstly, biomarkers based on mtDNA methylation will aid in early diagnosis of PD. These biomarkers will also make possible the use of interventions specific to the cause of disease (personalized therapy). Lastly, the discovery of changes in mtDNA associated with Parkinson's, such as methylation, will open avenues for development of new treatment strategies, since changes in methylation are largely reversible. Next Steps for Development: Identified biomarkers will need to be confirmed before they enter clinical practice. This will be achieved through additional retrospective and prospective studies, including clinical trials. |
| Searching for [Studies of 31P MRS] with PINK1 and PRKN Mutations | https://www.michaeljfox.org/grant/... |
Study Rationale: PINK1 and parkin are two proteins that work together to keep cells healthy by ridding them of damaged mitochondria, cells' powerhouses. Mutations (changes) in PINK1 and PRKN genes are associated with mitochondrial breakdown and the appearance of disease, especially in younger people. |
Uncertain Spans
| location | transcription | uncertainty |
|---|---|---|
Mitofusin Ubiquitination row left column annotation | reads Ps65-ub (?)를 WBC 에서 보는 듯 (Korean shorthand annotation in the title cell). | confidence on whether Ps65-ub here refers to the same pS65-Ub token used elsewhere on the page (uppercase vs. lowercase). |
pS65-Ub as a Biomarker / PI block | reads Mayo Clinic / Wolfdieter Springer reconstructed from the partial OCR ayo Clinic / olfdieter / inger. | low confidence on the exact spelling of the PI’s first name (Wolfdieter vs. Olfdieter); preserved as Wolfdieter Springer per public Mayo Clinic record convention. |
URLs in middle column | URLs visible in the source are partially clipped on the right edge; rendered as https://www.michaeljfox.org/grant/... placeholders for the truncated parts. | URL slugs reconstructed from visible fragments. |
Searching for Studies of 31P MRS with PINK1 and PRKN Mutations row title | the title is reconstructed from the side-nav bleed Studies of 31P MRS / Oliver Bandmann, MD,... / MELAS (Mitochondrial enc...) and the body text fragment with PINK1 and PRKN Mutations. | partial header. |