Amyotrophic lateral sclerosis (ALS) is a rapidly progressive and fatal degenerative disease affecting the nerve cells in the brain and spinal cord responsible for controlling voluntary muscle movement. Sporadic or non-inherited ALS, accounts for roughly 90% percent of cases, and 10% of cases are due to known genetic mutations. By studying lab-grown neurons derived from skin or blood cells from 10 normal controls, eight with an ALS causing mutation, and 17 with non-inherited ALS, researchers have found a possible starting point for the dysfunction that causes the disease. The study, which was published in Science Translational Medicine was funded in part by the National Institute for Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health.
Using a library of ALS patient-derived cells, the research team led by Jeffrey Rothstein, M.D., Ph.D., at Johns Hopkins University School of Medicine, Baltimore, developed induced pluripotent stem cell (iPSC)-derived neurons from the patients cultured cells to discover a common defect regardless of whether the cell came from persons with inherited or non-inherited ALS. They report that in ALS nerve cells, there is an accumulation of a protein called CHMP7 in the nucleus of cultured nerve cells as well as in ALS samples from the brain region that controls movement. Treatments that decrease the amount of CHMP7 in the cultured cells prevented a series of abnormalities that are characteristic of ALS.
There is considerable interest in identifying new therapeutic targets for ALS, particularly for the sporadic form of the disorder, said Amelie Gubitz, Ph.D., program director, NINDS. Gene-targeting strategies like the one shown here now allow us to move from biological discovery straight to therapy development.
This study builds on an earlier paper by the Rothstein lab that looked at the most common genetic cause of ALS, a mutation in the C9orf72 gene (also referred to as the C9 mutation). There, they showed that the C9 mutation produced defects in a structure called the nuclear pore that is responsible for moving proteins and other molecules in and out of the nucleus of cells. Specifically, they found that certain proteins were absent from the pore, causing a domino-like effect in which the entire pore breaks apart.
We knew from our previous work that the C9 mutation was producing defects in the nuclear pore, but we didnt know why, said Dr. Rothstein. Here, we set out to answer the question of what was happening upstream of the pore defects by studying neurons derived from the cells of patients with ALS.
Specifically, the researchers looked at nerve cells grown from induced pluripotent stem cells (iPSCs), which are a type of stem cell that can be created from samples of a persons skin or blood. These cells behave very much like other stem cells in that they can be turned into many different cell types in a lab setting, including nerve cells. By working with Answer ALS, a national ALS biological data and iPSC effort run by Rothstein, the researchers were able to access iPSCs derived from both familial and sporadic ALS patients.
One of the great advantages of iPSCs is that you can look at different times very much in the same way as you would study animal models at different ages, said Dr. Rothstein. We knew the time point where the nuclear pores began to degrade, and we were able to study neurons at earlier times to see what the cause could be.
What they found was that the accumulation of CHMP7 within the nucleus occurred at least one week prior to the development of nuclear pore abnormalities. Normally, CHMP7 is quickly removed once it enters the nucleus, but in both C9 and sporadic ALS iPSC-derived neurons, the accumulation persisted. If an antisense oligonucleotide drug, which stops cells from manufacturing specific proteins, was used to decrease the amount of CHMP7 within the ALS neurons, the pore never degraded. Finally, if a mutated form of CHMP7 that cannot be removed from the nucleus was added to healthy neurons, the pore degraded much like what was seen in ALS neurons, suggesting that the presence of CHMP7 within the nuclei of neurons could be a lynchpin event in the development of the disease.
One abnormality common to all forms of ALS is the mislocalization of another protein, TDP-43. Normally found in the nucleus, TDP-43 leaks out into the surrounding cytoplasm in ALS where it clumps together into aggregates, leading to loss of function changes in various types of RNA, which are critical for the translation of certain genes into proteins. Eventually this is also seen in iPSC-derived neurons from both C9 and sporadic ALS patients. Following treatment with the antisense oligonucleotides for CHMP7, the TDP-43 mislocalization was no longer seen and the RNA defects were all corrected.
These findings together allow us to put these abnormalities in sequence, where CHMP7 accumulation in the nucleus leads to nuclear pore injury, followed by TDP-43 mislocalization, and ultimately cell death, said Dr. Rothstein. This is not just limited to the C9 mutation; it is a fundamental pathway in sporadic ALS as well that can be treated with antisense oligonucleotides for CHMP7.
Dr. Rothsteins lab is currently investigating whether the antisense oligonucleotide drug could be developed into a treatment for both C9 and sporadic ALS patients. They are also continuing to study the initial accumulation of CHMP7 to determine what causes the mislocalization in the nucleus.
Reference:Coyne AN, Baskerville V, Zaepfel BL, et al. Nuclear accumulation of CHMP7 initiates nuclear pore complex injury and subsequent TDP-43 dysfunction in sporadic and familial ALS. Sci. Transl. Med. 2021;13(604). doi:10.1126/scitranslmed.abe1923
This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.
Originally posted here:
Protein Discovery Links Together Two Forms of ALS - Technology Networks
- One year to test 200 Cordlife samples 'totally unjustified': Global cord blood banking experts - The Straits Times - April 15th, 2024
- Clinical trial: First cardiac bioimplants for treatment of myocardial infarction using umbilical cord stem cells - Medical Xpress - April 7th, 2024
- The umbilical cord: a rich and ethical stem cell source to advance ... - March 30th, 2024
- Story of discovery: getting a Notch up on cord blood cell ... - March 30th, 2024
- Cord Blood Transplants | Memorial Sloan Kettering Cancer Center - March 30th, 2024
- Therapeutic effect and study of human umbilical cord blood mononuclear cells in patients with ischaemic bowel ... - Nature.com - March 17th, 2024
- Global Cord Blood & Tissue Banking Industry Report 2024: The Vast Majority of the Global Cord Blood Market is Now ... - PR Newswire - March 15th, 2024
- Improving Transplant Outcomes and Cell Therapy Approaches - RegMedNet - March 9th, 2024
- The inhibition of ADAM17 in cord blood stem cell-derived CD16+ NK cells to enhance their cytotoxicity against acute ... - ScienceDirect.com - March 1st, 2024
- Beating Blood Cancer through Recycling - a Community crowdfunding project in Liverpool by Kate Williams - Crowdfunder UK - February 24th, 2024
- Cord Blood Registry (CBR ) by CooperSurgical and Fulgent Genetics Launch Innovative Genetic Testing - Investing.com Canada - February 9th, 2024
- Young cancer patient with 'no hope' of recovery saved by baby's umbilical cord - Study Finds - February 9th, 2024
- Global Cord Blood & Tissue Banking Industry Report 2024 - The Vast Majority of the Global Cord Blood Market is Now ... - ACROFAN - January 26th, 2024
- Finding the optimal combination of anticancer drug administration for the conditioning of cord blood transplantation - Medical Xpress - January 26th, 2024
- Cord Blood Banking Market Sales and Revenue Report 2023-2032 - WhaTech Technology and Markets News - January 26th, 2024
- Global Cord Blood & Tissue Banking Industry Report 2024 - The Vast Majority of the Global Cord Blood Market is Now ... - ACROFAN USA - January 24th, 2024
- Global Biobanking Market Size To Exceed USD 97.5 Billion By 2032 | CAGR of 5.8% - GlobeNewswire - January 24th, 2024
- The use of cryopreservation in life saving research - The Manufacturer - January 24th, 2024
- CD19-targeted CAR NK cell therapy achieves promising one-year results in patients with B-cell malignancies - Medical Xpress - January 18th, 2024
- Cord blood banking comes at a high cost to babies - STAT - STAT - January 18th, 2024
- Global Cord Blood and Tissue Banking Industry Gains Traction Amidst Surging M&A Activity and Technological Advances - PR Newswire - January 16th, 2024
- Donating Bone Marrow and Stem Cells: The Process and What To Expect - On Cancer - Memorial Sloan Kettering - January 11th, 2024
- Ask the doctors: Research being conducted on using stem cells to treat diabetes - The Spokesman Review - January 4th, 2024
- askST: Can cord blood units be transferred from one bank to another? - The Straits Times - December 27th, 2023
- Timeline: Cordlife's mishandling of cord blood units in Singapore - CNA - December 15th, 2023
- Next-Level Evolution: Enhancing the Human Body With Anthrobots ... - Securities.io - December 5th, 2023
- Fred Hutch at ASH: Gene therapies for sickle cell, how to improve ... - Fred Hutchinson Cancer Center - December 5th, 2023
- Enhancing the immunosuppressive properties of human umbilical ... - Phys.org - December 1st, 2023
- Global Status and Trends for Thromboangiitis Obliterans | JPR - Dove Medical Press - December 1st, 2023
- Early Stage Cell Therapy Trial Shows Promise in Treating Progressive Multiple Sclerosis - University of Colorado Anschutz Medical Campus - December 1st, 2023
- Global Medical Specialty Bag Market is Expected to Reach US$ 9.4 Billion by 2034, Rising at a Steady 4.7% CAGR | Future Market Insights, Inc. - Yahoo... - November 29th, 2023
- Repeated concussions can alter heart activity and impact the heart ... - Philippine Canadian Inquirer - November 29th, 2023
- Vita 34 increases revenue and earnings in Q3 2023 and further ... - PharmiWeb.com - November 27th, 2023
- Vita 34 increases revenue and earnings in Q3 2023 and further ... - Marketscreener.com - November 25th, 2023
- FY 2021 VA-Funded Projects - VA's Office of Research and Development - November 25th, 2023
- New study aims to expand access to stem cell transplant using ... - Healio - November 23rd, 2023
- Impact of GVHD Prophylaxis on CMV Reactivation and Disease ... - Cancer Network - November 23rd, 2023
- The Top 25 Women Leaders in Biotechnology of 2023 - The Healthcare Technology Report. - November 21st, 2023
- First Edition: November 20, 2023 - KFF Health News - November 21st, 2023
- An essential guide to the building blocks of life - Gates Notes - November 21st, 2023
- A Simple Way to Save Premature Babies - The New York Times - November 19th, 2023
- Perspectives of current understanding and therapeutics of Diamond ... - Nature.com - November 17th, 2023
- Brain Organoids: Should They Be Considered People? - BBVA OpenMind - November 17th, 2023
- Understanding the cause of childhood Alzheimer's - ASBMB Today - November 17th, 2023
- Peripheral nerve regeneration through nanofiber scaffolds | IJN - Dove Medical Press - November 15th, 2023
- Are STEM CELL EXOSOMES the secret to a 'snatched' jawline? Discover the products that influencers are claiming - Daily Mail - November 13th, 2023
- CAR-NK: The next generation in hematological malignancy treatment - News-Medical.Net - November 13th, 2023
- Regenerative Medicine | Top Regenerative Medicine Solution ... - Healthcare Tech Outlook - November 13th, 2023
- Stem cell therapy, emerging solution to slow down ageing - Punch Newspapers - November 13th, 2023
- Improving Cord Blood Transplantation Outcomes for Adults With ... - On Cancer - Memorial Sloan Kettering - November 11th, 2023
- 8 Ways To Save Lives With Canadian Blood Services & You Can ... - Narcity Canada - November 11th, 2023
- Internal investigation by Vita 34 AG reveals irregularities related to a ... - Marketscreener.com - November 11th, 2023
- 'We worried the worst would happen' - Yorkshire Children's Trust ... - The Yorkshire Post - November 11th, 2023
- Minor GPI(-) granulocyte populations in aplastic anemia and healthy ... - Nature.com - November 9th, 2023
- Repeated treatment with ProTrans is immunologically safe ... - Marketscreener.com - November 7th, 2023
- Affimed Announces Oral Presentation of Phase 1/2 Data from AFM13 in Combination with Allogeneic NK Cells - Benzinga - November 7th, 2023
- Health Canada issues warning on cord blood stored in Edmonton - CBC News - November 3rd, 2023
- Affimed Announces Oral Presentation of Phase 1/2 Data from AFM13 in Combination with Allogeneic NK Cells at the 2023 ASH Annual Meeting - Yahoo... - November 3rd, 2023
- Dynamic Stem Cell Therapy Uncovers Research in Advance ... - InvestorsObserver - November 3rd, 2023
- Go with the flow and achieve hearing restoration - Drug Discovery News - November 3rd, 2023
- Cell Therapy Market to Witness Exponential Growth by 2031 ... - Argyle Report - November 1st, 2023
- Cross-talk between Myeloid and B Cells Shapes the Distinct ... - Cancer Discovery - November 1st, 2023
- Comparison of effects of HucMSCs, exosomes, and conditioned ... - Nature.com - October 28th, 2023
- The structural and functional complexity of the integrative ... - Science - October 28th, 2023
- Global Primary Cells Market to Witness Growth at 11.41% CAGR to ... - GlobeNewswire - October 26th, 2023
- Hma-Qubec celebrates 25 years of giving life in anniversary ad - - The Message - October 26th, 2023
- Improvement of thermal-stability of chondroitinase ABCI immobilized ... - Nature.com - October 26th, 2023
- Sydney Couple Overcomes Sperm Antibody Issue to Welcome Baby - OPP.Today - October 24th, 2023
- New Research Reveals Surprising Issue with Sperm and Fertility - CityLife - October 24th, 2023
- Biobanking Market to Observe Prominent CAGR of 6.10% by 2029 ... - PharmiWeb.com - October 21st, 2023
- TV shows like BBC's Call The Midwife and C4's One Born Every Minute 'are inaccurately depicting childbirth' an - Daily Mail - October 19th, 2023
- Advances in medical and technological research and SCI - Clyde & Co - October 18th, 2023
- Prognostic Value of Hematogones in Patients With Hematopoietic ... - Cureus - October 18th, 2023
- Stem-Cell Therapy: Filling Gaps in Oro-Maxillofacial Region - Cureus - October 18th, 2023
- The neonatal southern white rhinoceros ovary contains oogonia in ... - Nature.com - October 18th, 2023
- OMG: Sperm injury led to rare baby struggle - news.com.au - October 18th, 2023
- Experts Explain how MS Impacts the Eyes and Eye Health - Health Central - October 18th, 2023
- Newly identified stem cells can lure breast cancer to the spine - Science News Magazine - October 15th, 2023
- Cases of HIV cure | aidsmap - aidsmap - October 15th, 2023
- HokUS-10 scoring system predicts the treatment outcome for ... - Nature.com - October 13th, 2023
Recent Comments