The value of patient-based cell models and brain organoids in unpicking the complexities of neurodegenerative diseases is again highlighted in new research showing how mutations that cause a rare subtype of Parkinson's disease operate at a cellular level.
Using stem cells derived from members of families carrying mutations in the PARK7 gene that are linked to an early onset form of Parkinson's disease, the researchers at the University of Luxembourg directly observed that these defects disrupt exon splicing.
That interferes with the activity of a small RNA called U1, reducing production of the DJ-1 protein (also called Parkinsonism associated deglycase), which among other functions, is involved in mitochondrial regulation. The researchers found that mitochondria in the patient-derived cell models malfunctioned as a result.
Based on this insight, Ibrahim Boussaad and colleagues designed a combination therapy that repaired these aberrations, halting the death of dopaminergic neurons in brain organoids.
The researchers say the study, published in the latest issue of Science Translational Medicine, provides a foundation to develop therapies that could help correct the genetic cause of some forms of Parkinson's disease.
"When PARK7 was first discovered it was described as causing the substitution of an amino acid. It's only when we got patient material we could see it's not substitution. We saw it was a problem with splicing," Boussaad told BioWorld Science.
There are more than 25 PARK7 gene mutations that are implicated in Parkinson's disease. However, it previously was unclear how loss of functional DJ-1 protein causes the neurodegenerative disease, with some studies suggesting PARK7 mutations disrupt the protein's chaperone function, leading to a toxic buildup of misfolded proteins, while others suggest PARK7 mutations impair DJ-1's ability to protect cells from oxidative stress.
Boussaad said the researchers were aiming to pinpoint specific defects in the mutant DJ-1 protein generated by the patient cell models. Instead, they found there was little or no trace of the protein at all.
The possibility that the protein was unstable and had degenerated was excluded by blocking degradation pathways to show there were no metabolites of the protein.
"So we took a step back and started to look upstream. We could detect [PARK7] RNA, but it was shorter," said Boussaad. "On sequencing the products, we saw an entire section of RNA was missing."
Luckily, one of the donors was heterozygous for PARK7, and in this case it was possible to detect both normal length and shorter RNA, helping to confirm that mis-splicing was blocking DJ-1 production.
The researchers showed it was possible to correct the defective exon skipping using genetically engineered U1-snRNA (small nuclear RNA). That corrected DJ-1 expression in neuronal precursor cells and differentiated neurons.
They also demonstrated that combination treatment with the small molecules RECTAS (rectifier of aberrant splicing) and phenylbutyric acid repaired the splicing defects, restoring DJ-1 production, correcting mitochondrial function and preventing loss of dopaminergic cells in mutant PARK7 brain organoids.
Looking at sequence databases, the researchers found that similar splicing mutations appeared more frequently in the genomic data from 2,710 patients with the common sporadic form of Parkinson's disease, than in data from 5,713 controls, pointing to a wider significance of the current study.
With the literature suggesting that as many as a third of all disease-causing mutations exert their effects through faulty exon splicing, the findings could also have relevance to other conditions.
The direct observation of the cellular-level impact of one of these mutations and the possibility of therapeutic intervention, should lead to greater focus in this area, Boussaad said. "There are a few other such mutations known and described, but they have not got the attention they should have in the field of neurodegenerative diseases."
As a next step, the researchers plan to further develop the combination treatment. "We are going into animal models to see how potent it is in entire organisms. We also want to look at availability in the brain and if compounds have the ability to cross the blood-brain barrier," said Boussaad. "And of course, the other direction will be to further explore the abundance of exon splicing mutations in Parkinson's disease."
It is becoming increasingly clear that although patients with Parkinson's present with the same motor symptoms, there are subtypes of the disease which have different etiologies. "To advance treatment, we have to stratify. We have to investigate for each patient, why they have this disease," Boussaad said.
That could form the basis of customized treatments. "If we can identify patients with exon splicing mutations it will have positive benefits. If they can be corrected, it will restore the protein and be neuroprotective, rather than treating the symptoms," said Boussaad. "It could have a significant impact." (Boussaad, I. et al. Sci Transl Med 2020, 12: eaau3960).
Read the original post:
- Stem Cell Therapies: Is This The Future Of Wellness? - Grazia USA - April 20th, 2024
- Signal of Benefit for Stem Cell Therapy in Progressive MS - Medscape - March 7th, 2024
- The Controversies Surrounding Stem Cell Therapy for Autism - The Portugal News - February 24th, 2024
- Benefits of Stem Cell Therapy - News Channel 5 Nashville - February 7th, 2024
- What is Stem Cell Therapy & How It Helps Others - Publicist Paper - January 31st, 2024
- A guide to stem cell therapy in Thailand - Thaiger - January 4th, 2024
- Half of pediatric patients with aHUS benefit from Soliris after... - AHUS News - December 21st, 2023
- Real world analysis on the determinants of survival in primary ... - Nature.com - December 5th, 2023
- The Best Beauty Gifts According To People Who Really Know Skin Care - HuffPost - December 5th, 2023
- The Eyepopping Factory Construction Boom in the US - WOLF STREET - December 3rd, 2023
- Benefit of Neoadjuvant Therapy Illustrated During ESMO Congress ... - Targeted Oncology - December 1st, 2023
- Benefits Outweigh Risks as FDA Inspects CAR-T Cell Therapy ... - Curetoday.com - December 1st, 2023
- Review What Real Cavityn Customers Say About Benefits and Side ... - Seattle Weekly - December 1st, 2023
- 'There is a Scientific Fraud Epidemic' - Slashdot - Slashdot - December 1st, 2023
- 15 Best Hydrating Serums to Soothe Any Skin Type 2023 - Town & Country - December 1st, 2023
- Innovations in Cosmetic Dermatology: A Glimpse into the Future - APN News - December 1st, 2023
- FDA Probes New Cases of Cancer That May Stem From Cancer Cell ... - MedCity News - November 29th, 2023
- Use of plant stem cells in topical formulations on the rise - CosmeticsDesign.com USA - November 29th, 2023
- Stem cell-based treatment controls blood sugar in people with Type ... - EurekAlert - November 29th, 2023
- Biologics Market is projected to grow at a CAGR of 8.5% by 2034: Visiongain - Yahoo Finance - November 29th, 2023
- Scientists devise new technique that can pinpoint the causes and ... - EurekAlert - November 29th, 2023
- Global Advanced Therapy Medicinal Products Market is on the brink ... - PharmiWeb.com - November 29th, 2023
- Introducing Orgavalue - The 2023 EIT InnoStars Awards winner - EU-Startups - November 29th, 2023
- Episode 160: Euan Ashley discusses precision medicine and the ... - IHMC - November 29th, 2023
- Is Phenq Right For You? Review The Facts Before Making a ... - Vashon-Maury Island Beachcomber - November 27th, 2023
- Cavityn Reviews - Does It Work? Cheap Scam or Effective ... - The Daily World - November 25th, 2023
- Trend Hunting With Beautystreams At Cosmoprof Asia 2023 - BeautyMatter - November 25th, 2023
- FDA Considers First CRISPR Gene Editing Treatment That May ... - Slashdot - November 25th, 2023
- How Do Plants Determine Where the Light Is Coming From? - Lab Manager Magazine - November 25th, 2023
- Deaths From Coal Pollution Have Dropped, But Emissions May be ... - Slashdot - November 25th, 2023
- Stem cell-based therapies for stroke in newborns - Cochrane - November 23rd, 2023
- Dr Leslie on Outpatient CAR T-Cell Therapy Programs for ... - OncLive - November 23rd, 2023
- Human Milk-Based Therapy May Be Beneficial in Blood Cancers - Curetoday.com - November 23rd, 2023
- Oncological Horizons: The Synergy of Medical and Surgical ... - Cureus - November 23rd, 2023
- Human and environmental safety of carbon nanotubes across their ... - Nature.com - November 23rd, 2023
- Immix Biopharma to Host KOL Event to Discuss its BCMA-Targeted ... - BioSpace - November 23rd, 2023
- #HearTheMarsdenKids call on NHS London to reconsider cancer ... - Metro.co.uk - November 23rd, 2023
- Diagnosis and Management of Cardiovascular Risk in Patients with ... - Dove Medical Press - November 23rd, 2023
- BioLineRx Reports Third Quarter 2023 Financial Results and ... - PR Newswire - November 21st, 2023
- Why our Award Winners Beauty Box is the ultimate beauty gift (for ... - Yahoo Singapore News - November 21st, 2023
- SightCare Reviews - Is Official Website for Sight Care Legit to Try or ... - Vashon-Maury Island Beachcomber - November 21st, 2023
- Legend Biotech Reports Third Quarter 2023 Results and Recent ... - StreetInsider.com - November 21st, 2023
- Lorenzo's Oil: Can It Really Treat ALD? - Verywell Health - November 19th, 2023
- Doctor Says Living To 120 By End Of Decade Is Possible What's the Secret? - Benzinga - November 19th, 2023
- The week in pharma: action, reaction and insight week to ... - The Pharma Letter - November 19th, 2023
- Race Cannot Be Used To Predict Heart Disease, Scientists Say ... - Slashdot - November 19th, 2023
- SpaceX's Starship Reaches Outer Space Before Intentional ... - Slashdot - November 19th, 2023
- Mesenchymal Stem Cells Market is projected to reach USD 3,319 million by 2030 according to a new research r... - WhaTech Technology and Markets News - November 17th, 2023
- LMRUK: Protecting the next generation through cord blood - Charity Today News - November 17th, 2023
- Anti-aging molecule discovered that extends lifespan - Earth.com - November 17th, 2023
- Montana State researcher envisions living building materials that ... - Montana State University - November 17th, 2023
- OxyHelp Explores the Benefits of Hyperbaric Oxygen Therapy for ... - StreetInsider.com - November 15th, 2023
- Health benefits of bone marrow - Pakistan Observer - November 15th, 2023
- Evolving the standard of care: What is next for functional ... - NeuroNews International - November 15th, 2023
- Affimed Reports Third Quarter 2023 Financial Results and ... - BioSpace - November 15th, 2023
- Meet the World's First Whole-Eye Transplant Recipient - TIME - November 15th, 2023
- Calidi Biotherapeutics Reports Third Quarter 2023 Operating and ... - Business Wire - November 15th, 2023
- 10 Asia-Pacific biotech companies leading innovation in the region - Labiotech.eu - November 15th, 2023
- Fitspresso Reviews (November Update) Natural Ingredients That ... - Bainbridge Island Review - November 15th, 2023
- 2seventy bio Reports Third Quarter Financial Results and Recent ... - Business Wire - November 15th, 2023
- Japan To Create $6.6 Billion Fund To Develop Outer Space Industry ... - Slashdot - November 15th, 2023
- Be The Match, Healthcare Marketing Impact Awards 2023 - Ad Age - November 13th, 2023
- Medicare coverage saves lives. Enrolling shouldn't be this ... - Kevin MD - November 13th, 2023
- Future Ocean Foods: 36 Global Alt-Seafood Startups Form Association To Tackle Overfishing, Microplastics & More - Green Queen Media - November 13th, 2023
- Orchard Therapeutics Reports Third Quarter 2023 Financial Results ... - StreetInsider.com - November 13th, 2023
- Celebrity doctor reveals Hollywoods hidden trend of stem cell antiaging therapies - Longevity.Technology - November 11th, 2023
- Amazon Expands Healthcare Push With One Medical Benefits For ... - Slashdot - November 11th, 2023
- Bene Meat Technologies becomes the first to receive EU approval ... - Pet Food Processing - November 11th, 2023
- FDA Grants Orphan Drug Designation to MAIA Biotechnology for THIO as a Treatment for Glioblastoma - Yahoo Finance - November 11th, 2023
- MaaT Pharma Provides Third Quarter 2023 Business Update and ... - Business Wire - November 11th, 2023
- IN8bio Reports Third Quarter 2023 Financial Results and Provides ... - GlobeNewswire - November 11th, 2023
- Fast Lean Pro Reviews - Overpriced or Optimal Ingredients That ... - Journal of the San Juan Islands - November 11th, 2023
- Fate Therapeutics Reports Third Quarter 2023 Financial Results and ... - GlobeNewswire - November 11th, 2023
- Worlds first whole-eye and partial face transplant gives Arkansas man new hope - CNN - November 9th, 2023
- Glowing Fingertips And Green Eyes: First-of-Its-Kind Monkey ... - ScienceAlert - November 9th, 2023
- 10 Natural Body Scrubs That Exfoliate And Invigorate My Skin - PINKVILLA - November 9th, 2023
- CRISPR Therapeutics Provides Business Update and Reports Third ... - StreetInsider.com - November 9th, 2023
- Fate Therapeutics Reports Third Quarter 2023 Financial Results and ... - StreetInsider.com - November 9th, 2023
- Sight Care Reviews - Overpriced or Worth the Hype? SightCare Pills ... - Journal of the San Juan Islands - November 9th, 2023
- 6 Amazing Health Benefits Of Giloy (Tinospora cordifolia) - WION - November 9th, 2023
Recent Comments