AI Article Synopsis
- Canavan disease is a genetic disorder caused by a mutation in the aspartoacylase gene, leading to a buildup of N-acetylaspartate that disrupts water balance in the brain.
- Research using a mouse model of the disease showed age-related motor impairment and brain degeneration, particularly affecting regions like the basal ganglia and cerebellum.
- Changes in aquaporin 4 localization in astrocytes suggest that targeting this water channel could offer therapeutic potential for managing Canavan disease.
Article Abstract
Canavan disease is a spongiform leukodystrophy caused by an autosomal recessive mutation in the aspartoacylase gene. Deficiency of oligodendroglial aspartoacylase activity and a subsequent increase of its substrate N-acetylaspartate are the etiologic factors for the disease. N-acetylaspartate acts as a molecular water pump. Therefore, an osmotic-hydrostatic mechanism is thought to be involved in the development of the Canavan disease phenotype. Astrocytes express water transporters and are critically involved in regulating and maintaining water homeostasis in the brain. We used the ASPA(Nur7/Nur7) mouse model of Canavan disease to investigate whether a disturbance of water homeostasis might be involved in the disease's progression. Animals showed an age-dependent impairment of motor performance and spongy degeneration in various brain regions, among the basal ganglia, brain stem, and cerebellar white matter. Astrocyte activation was prominent in regions which displayed less tissue damage, such as the corpus callosum, cortex, mesencephalon, and stratum Purkinje of cerebellar lobe IV. Immunohistochemistry revealed alterations in the cellular distribution of the water channel aquaporin 4 in astrocytes of ASPA(Nur7/Nur7) mice. In control animals, aquaporin 4 was located exclusively in the astrocytic end feet. In contrast, in ASPA(Nur7/Nur7) mice, aquaporin 4 was located throughout the cytoplasm. These results indicate that astroglial regulation of water homeostasis might be involved in the partial prevention of spongy degeneration. These observations highlight aquaporin 4 as a potential therapeutic target for Canavan disease.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1007/s12031-013-0184-4 | 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.
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 PDFAmyloid-like Aggregation Propensities of Metabolites- Homogentisic Acid, N-Acetyl Aspartic Acid and Isovaleric Acid.
Chembiochem
December 2024
Department of Chemistry, Indrashil University, Kadi, Mehsana, Gujarat, India.
The transformation of metabolites into amyloidogenic aggregates represent an intriguing dimension in the pathophysiology of metabolic disorders, including alkaptonuria, canavan disease, and isovaleric acidemia. Central to this phenomenon are the metabolites homogentisic acid (HA), N-acetyl aspartic acid (NAA), and isovaleric acid (IVA), which we found, weave an intricate network of self-assembled structures. Leveraging an array of microscopy techniques, we traced the morphological behavior of these assemblies that exhibit concentration and time-dependent morphological transitions from isolated globules to clustered aggregates.
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!