Canavan disease, a leukodystrophy caused by loss-of-function ASPA mutations, is characterized by brain dysmyelination, vacuolation, and astrogliosis ("spongiform leukodystrophy"). ASPA encodes aspartoacylase, an oligodendroglial enzyme that cleaves the abundant brain amino acid N-acetyl-L-aspartate (NAA) to L-aspartate and acetate. Aspartoacylase deficiency results in a 50% or greater elevation in brain NAA concentration ([NAA]). Prior studies showed that homozygous constitutive knockout of Nat8l, the gene encoding the neuronal NAA synthesizing enzyme N-acetyltransferase 8-like, prevents aspartoacylase-deficient mice from developing spongiform leukodystrophy. We now report that brain Nat8l knockdown elicited by intracerebroventricular/intracisternal administration of an adeno-associated viral vector carrying a short hairpin Nat8l inhibitory RNA to neonatal aspartoacylase-deficient Aspa mice lowers [NAA] and suppresses development of spongiform leukodystrophy.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5910673 | PMC |
| http://dx.doi.org/10.1016/j.ymthe.2018.01.002 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Urine -Acetylaspartate Distinguishes Phenotypes in Canavan Disease.
Hum Gene Ther
December 2024
BridgeBio Gene Therapy, Palo Alto, California, USA.
Article Synopsis
- Canavan disease (CD) is a rare genetic disorder caused by mutations in the ASPA gene, leading to high levels of N-acetylaspartate (NAA) in the body and severe developmental issues in infants.
- A subset of patients displays milder symptoms, possibly due to some remaining ASPA activity, raising the question of how urine NAA levels relate to this.
- A study found that individuals with the mild phenotype had significantly lower urine NAA levels and specific ASPA mutations that were absent in those with the typical phenotype, indicating that urine NAA can be used to differentiate between the two types of CD.
N-acetylaspartate mitigates pro-inflammatory responses in microglial cells by intersecting lipid metabolism and acetylation processes.
Cell Commun Signal
November 2024
Department of Biology, University of Rome Tor Vergata, Rome, 00133, Italy.
Background: Microglia play a crucial role in brain development and repair by facilitating processes such as synaptic pruning and debris clearance. They can be activated in response to various stimuli, leading to either pro-inflammatory or anti-inflammatory responses associated with specific metabolic alterations. The imbalances between microglia activation states contribute to chronic neuroinflammation, a hallmark of neurodegenerative diseases.
View Article and Find Full Text PDFAssociation of Vascular Risk With Severe vs Non-Severe Stroke: An Analysis of the INTERSTROKE Study.
Neurology
December 2024
From the HRB Clinical Research Facility Galway (C.R., M.C., C.J., M.J.O.), School of Medicine, University of Galway; Wellcome Trust-HRB (C.R.), Irish Clinical Academic Training, Dublin, Ireland; Institute of Health Informatics (C.R.), University College London, United Kingdom; Perron Institute Chair in Stroke Research (G.J.H.), Medical School, The University of Western Australia; Perron Institute for Neurological and Translational Science (G.J.H.), Perth, Australia; Rush Alzheimer Disease Research Center (S.O.), Rush University Medical Center, Chicago, IL; Academic Section of Geriatric Medicine (P.L.), Glasgow Royal Infirmary, University of Glasgow, United Kingdom; Beijing Hypertension League Institute (X.W.), China; Health and Medical Sciences (H.K.I.), University of Copenhagen, Denmark; Faculty of Medicine (F.L.), Universidad de La Frontera, Temuco, Chile; King Saud University (F.A.-H.), Riyadh, Saudi Arabia; Institute of Psychiatry and Neurology (A.C.), Warsaw, Poland; Department of Internal Medicine (A.O.), Faculty of Medicine, Istanbul Medeniyet University, Turkey; Sahlgrenska University Hospital and Sahlgrenska Academy (A.R.), University of Gothenburg, Sweden; St Johns Medical College and Research Institute (D.X.), Bangalore, India; and Population Health Research Institute (S.Y., M.J.O.), Hamilton Health Sciences and McMaster University, Ontario, Canada.
Background And Objectives: Acute stroke is associated with a spectrum of functional deficits. The objective of this analysis was to explore whether the importance of individual risk factors differ by stroke severity, which may be of relevance to public health strategies to reduce disability.
Methods: INTERSTROKE is an international case-control study of risk factors of first acute stroke (recruitment 2007-August 2015) in 32 countries.
Treatment Patterns and Clinical Outcomes in Patients With EGFR-Mutated Non-Small-Cell Lung Cancer After Progression on Osimertinib.
Clin Lung Cancer
January 2025
Yale University School of Medicine, New Haven, CT. Electronic address:
Introduction: For patients with advanced epidermal growth factor receptor (EGFR)-mutated non-small-cell lung cancer (NSCLC) who progress on first-line osimertinib, the optimal second-line treatment regimen after progression is not known. We sought to assess practice patterns and evaluate the association between different therapies and survival in patients with EGFR-mutated NSCLC following progression on first-line osimertinib.
Methods: Retrospective cohort study of patients who received first-line treatment with osimertinib using a population-based, multicenter nationwide electronic health record-derived deidentified database.
Loss of synovial tissue macrophage homeostasis precedes rheumatoid arthritis clinical onset.
Sci Adv
September 2024
Molecular Rheumatology, School of Medicine, Trinity College Dublin, Dublin, Ireland.
This study performed an in-depth investigation into the myeloid cellular landscape in the synovium of patients with rheumatoid arthritis (RA), "individuals at risk" of RA, and healthy controls (HC). Flow cytometric analysis demonstrated the presence of a CD40-expressing CD206CD163 macrophage population dominating the inflamed RA synovium, associated with disease activity and treatment response. In-depth RNA sequencing and metabolic analysis demonstrated that this macrophage population is transcriptionally distinct, displaying unique inflammatory and tissue-resident gene signatures, has a stable bioenergetic profile, and regulates stromal cell responses.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!