Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease
Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
Standard
Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease. / Grønbæk-Thygesen, Martin; Hartmann-Petersen, Rasmus.
I: Cell and Bioscience, Bind 14, Nr. 1, 45, 2024.Publikation: Bidrag til tidsskrift › Review › Forskning › fagfællebedømt
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Cellular and molecular mechanisms of aspartoacylase and its role in Canavan disease
AU - Grønbæk-Thygesen, Martin
AU - Hartmann-Petersen, Rasmus
N1 - Publisher Copyright: © The Author(s) 2024.
PY - 2024
Y1 - 2024
N2 - Canavan disease is an autosomal recessive and lethal neurological disorder, characterized by the spongy degeneration of the white matter in the brain. The disease is caused by a deficiency of the cytosolic aspartoacylase (ASPA) enzyme, which catalyzes the hydrolysis of N-acetyl-aspartate (NAA), an abundant brain metabolite, into aspartate and acetate. On the physiological level, the mechanism of pathogenicity remains somewhat obscure, with multiple, not mutually exclusive, suggested hypotheses. At the molecular level, recent studies have shown that most disease linked ASPA gene variants lead to a structural destabilization and subsequent proteasomal degradation of the ASPA protein variants, and accordingly Canavan disease should in general be considered a protein misfolding disorder. Here, we comprehensively summarize the molecular and cell biology of ASPA, with a particular focus on disease-linked gene variants and the pathophysiology of Canavan disease. We highlight the importance of high-throughput technologies and computational prediction tools for making genotype–phenotype predictions as we await the results of ongoing trials with gene therapy for Canavan disease.
AB - Canavan disease is an autosomal recessive and lethal neurological disorder, characterized by the spongy degeneration of the white matter in the brain. The disease is caused by a deficiency of the cytosolic aspartoacylase (ASPA) enzyme, which catalyzes the hydrolysis of N-acetyl-aspartate (NAA), an abundant brain metabolite, into aspartate and acetate. On the physiological level, the mechanism of pathogenicity remains somewhat obscure, with multiple, not mutually exclusive, suggested hypotheses. At the molecular level, recent studies have shown that most disease linked ASPA gene variants lead to a structural destabilization and subsequent proteasomal degradation of the ASPA protein variants, and accordingly Canavan disease should in general be considered a protein misfolding disorder. Here, we comprehensively summarize the molecular and cell biology of ASPA, with a particular focus on disease-linked gene variants and the pathophysiology of Canavan disease. We highlight the importance of high-throughput technologies and computational prediction tools for making genotype–phenotype predictions as we await the results of ongoing trials with gene therapy for Canavan disease.
KW - NAA
KW - NAAG
KW - Neurodegeneration
KW - Proteasome
KW - Protein degradation
KW - Protein folding
KW - Protein misfolding
KW - Protein quality control
KW - Protein stability
KW - VUS
U2 - 10.1186/s13578-024-01224-6
DO - 10.1186/s13578-024-01224-6
M3 - Review
C2 - 38582917
AN - SCOPUS:85189763865
VL - 14
JO - Cell & Bioscience
JF - Cell & Bioscience
SN - 2045-3701
IS - 1
M1 - 45
ER -
ID: 388825169