20240722_183514

Biochemical method?

(Inline figure: 31P-MRS / Parkin study composite — panel A: three brain MRI slices with hatched ROI boxes; panel B: three stacked 31P-MRS spectra with annotated peaks; panel C: β-ATP/Pi (arb. unit) bar chart, wt ~5.4 vs Parkin-/- ~4.4. Preserved as body_r01 evidence.)

MELAS (Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes)

• ONSET: CHILD
• Prevalence
  • a- one of more common conditions in a group known as mitochondrial diseases. Together, mitochondrial diseases occur in about 1 in 4,000 people.
• Pathophysiology

Mutations in mt DNA	impair the ability of	Lactic acidosis	Body location	Affected individuals experience
MT-ND1, MT-ND5, MT-TH, MT-TL1 (80% of cases), and MT-TV.	impair the ability of mitochondria to make proteins, use oxygen, and produce energy.	Lactic acidosis in most cases (↑ acidity)	Brain	Most affected individuals experience stroke-like episodes beginning before age 40. These episodes often involve temporary muscle weakness on one side of the body (hemiparesis), altered consciousness, vision abnormalities, seizures, and severe headaches resembling migraines. Repeated stroke-like episodes can progressively damage the brain, leading to vision loss, problems with movement, and a loss of intellectual function (dementia).
			Muscle	Muscle weakness, pain, easy cramping with exercise (myoclonus), impaired muscle coordination (ataxia), hearing loss, heart and kidney problems, diabetes, and hormonal imbalances
Cf) typical (this should be MT-TL1) A-to-G transition mutation at the nucleotide position 3243 of mtDNA (m.3243A>G) located in the tRNALeu(UUR)			blood	vomiting, abdominal pain, extreme tiredness (fatigue), muscle weakness, and difficulty breathing.

MJFF

Title	PI	Body
Novel Mitochondrial Biomarkers in Genetically Stratified Parkinson's Disease Patients https://www.michaeljfox.org/grant/novel-mitochondrial-biomarkers-genetically-stratified-parkinsons-disease-patients	Christine Klein, MD Lubeck, Germany	Study Rationale: Parkinson's disease has many causes and can be thought of as an umbrella term for patients with a diverse set of experiences. Research suggest dysfunction of mitochondria (e.g., the energy powerhouses of our cells) contributes to the development of Parkinson's disease. But this dysfunction is likely a major cause of the disease in only a specific group of patients with genetic mutations affecting mitochondria. In this study, we aim to identify a mitochondrial signature (i.e., biomarker) in people with genetic mutations as well as a group of patients with idiopathic (i.e., cause unknown) Parkinson's who have prominent mitochondrial dysfunction. Establishing and validating this biomarker is the aim of the present study. Hypothesis: We hypothesize that a mitochondrial signature in different groups of Parkinson's patients will have a higher degree of mitochondrial dysfunction. Study Design: We will establish and validate the biomarker of mitochondrial dysfunction in two different ways. First, we will assess the ability of mitochondria to produce energy by measuring the MMP in patient blood cells using a technique called fluorescence-activated cell sorting. Second, we will closely monitor metabolite turnover in the Cori cycle. The Cori cycle refers to the metabolic pathway in which lactate (produced in the muscles) moves to the liver where it is converted to glucose (sugar), which then returns to the muscles and is metabolized back to lactate. To follow this pathway that is indicative of mitochondrial function, we will use a special method called blood blood spot (DBS) gas chromatography/mass spectrometry (GC/MS). Both types of biomarkers will be obtained in patients and matched controls according to their degree of mitochondrial dysfunction. Impact on Diagnosis/Treatment of Parkinson's disease: Identifying patients with a high degree of mitochondrial dysfunction could inform clinical trial design as well as patient selection for clinical trials of drugs designed to enhance mitochondrial function. Next Steps for Development: Next steps will be to further validate the mitochondrial biomarker in independent patient cohorts and to use it for selection of patients for clinical trials testing drugs that specifically target mitochondrial function.
Studying the Production of Mitochondria to Find New Therapeutic Targets for Parkinson's Disease https://www.michaeljfox.org/grant/studying-production-mitochondria-find-new-therapeutic-targets-parkinsons-disease	Douglas Matthew Turnbull, MBBS, MD, PhD, MRCP Newcastle upon Tyne, United Kingdom	Study Rationale: It is known that the brain cells damaged in Parkinson's disease (PD) struggle to generate energy. This is because mitochondria — powerhouses of the cell — are faulty in these cells. These faulty mitochondria may hold the key to understanding what causes Parkinson's and how to treat it. Hypothesis: Our study will provide additional insight into the production of faulty mitochondria and will give us new therapeutic targets to treat this energy failure in patients with Parkinson's disease. Study Design: We will use brain samples and new technology to look inside individual brain cells. This technology allows us to look at many different components of the cell at the same time. This tells us how these components work together and how we might correct the abnormalities using drugs or cells producing better mitochondria. Impact on Diagnosis/Treatment of Parkinson's disease: In this study, we expect to find new therapeutic targets to treat people with PD. We also hope that if we can identify abnormal components of the cell, these might help in the diagnosis of PD. Next Steps for Development: If our research project is successful, we will look for drugs to act upon the identified targets. We will then test these drugs in the laboratory, and, if they work as expected, we will develop them for clinical use in people with Parkinson's disease.
Does Mitochondrial Dysfunction in the Skin Predict That in the Brain?		Study Rationale: Mitochondria — the power generators of the cell — do not function properly in Parkinson's disease (PD). This dysfunction, however, is not always present and can vary in its severity. We and other researchers found mitochondrial dysfunction outside of the brain, in the skin of people with PD, but it is not clear whether mitochondrial dysfunction in the skin reflects mitochondrial dysfunction in the brain. A modern brain imaging technique, 31P-Magnetic Resonance Spectroscopy (31P-MRS), allows an indirect measurement of mitochondrial function in the brain. Hypothesis: We will determine whether mitochondrial dysfunction outside of the brain, in the skin, reflects mitochondrial dysfunction in the brain. Study Design: We will recruit both people with PD and healthy volunteers into this study. Study participants will donate skin samples via this study from which the skin cells called fibroblast will be grown from the samples in vitro. This will allow us to assess mitochondrial function and shape outside of the brain. At the same time, we will assess the mitochondrial function in the brains of study participants using 31P-MRS. This will allow us to determine whether people with PD who have mitochondrial dysfunction in their skin cells also have mitochondrial dysfunction in their brain. Impact on Diagnosis/Treatment of Parkinson's disease: Our project will allow us to identify individuals with Parkinson's who are most likely to benefit from a mitochondria-targeting drug. These drugs are most likely to work in patients with particularly marked mitochondrial dysfunction. This approach — matching people with certain disease features to therapy most likely to help — is known as personalized medicine. Next Steps for Development: In the future, we will test drugs in peripheral tissues, such as skin, of individuals with PD before starting disease modifying treatment. We expect this approach to be much more powerful than treating all patients with the same drug and hoping that it will work equally well for everybody.

Pipeline C5aR1

Biochemical method?

Uncertain Spans

location	transcription	uncertainty
31P-MRS panel C bar chart	wt ~5.4 vs Parkin-/- ~4.4	y-axis tick spacing is approximate; values read from the small bar chart.
MELAS pathophysiology table	MT-ND1, MT-ND5, MT-TH, MT-TL1 (80% of cases), and MT-TV.	The trailing period inside MT-TV. mid-list could be a comma.
MJFF Klein study blood blood spot	blood blood spot (DBS) gas chromatography/mass spectrometry	Source has a doubled “blood blood”; preserved verbatim, may be a typo for “dried blood spot”.
MJFF “skin” study title	Does Mitochondrial Dysfunction in the Skin Predict That in the Brain?	The PI cell is empty on this capture; the study title is read from the navigation column in the source.