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4-Phenylbutyric Acid (4-PBA) Derivatives Prevent SOD1 Amyloid Aggregation In Vitro with No Effect on Disease Progression in SOD1-ALS Mice
- Source :
- International Journal of Molecular Sciences; Volume 23; Issue 16; Pages: 9403
- Publication Year :
- 2022
- Publisher :
- Multidisciplinary Digital Publishing Institute, 2022.
-
Abstract
- Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the degeneration of motor neurons. Mutations in the superoxide dismutase (SOD1) gene, causing protein misfolding and aggregation, were suggested as the pathogenic mechanisms involved in familial ALS cases. In the present study, we investigated the potential therapeutic effect of C4 and C5, two derivatives of the chemical chaperone 4-phenylbutyric acid (4-PBA). By combining in vivo and in vitro techniques, we show that, although C4 and C5 successfully inhibited amyloid aggregation of recombinant mutant SOD1 in a dose-dependent manner, they failed to suppress the accumulation of misfolded SOD1. Moreover, C4 or C5 daily injections to SOD1G93A mice following onset had no effect on either the accumulation of misfolded SOD1 or the neuroinflammatory response in the spinal cord and, consequently, failed to extend the survival of SOD1G93A mice or to improve their motor symptoms. Finally, pharmacokinetic (PK) studies demonstrated that high concentrations of C4 and C5 reached the brain and spinal cord but only for a short period of time. Thus, our findings suggest that use of such chemical chaperones for ALS drug development may need to be optimized for more effective results.
- Subjects :
- Amyloid
Superoxide Dismutase
Amyotrophic Lateral Sclerosis
Organic Chemistry
Amyloidogenic Proteins
Mice, Transgenic
Neurodegenerative Diseases
General Medicine
Butylamines
Phenylbutyrates
Catalysis
Computer Science Applications
Inorganic Chemistry
Disease Models, Animal
Mice
Superoxide Dismutase-1
Spinal Cord
Disease Progression
Animals
amyotrophic lateral sclerosis (ALS)
mutant SOD1
misfolded proteins
aggregation
chemical chaperones
Physical and Theoretical Chemistry
Molecular Biology
Spectroscopy
Molecular Chaperones
Subjects
Details
- Language :
- English
- ISSN :
- 14220067
- Database :
- OpenAIRE
- Journal :
- International Journal of Molecular Sciences; Volume 23; Issue 16; Pages: 9403
- Accession number :
- edsair.doi.dedup.....d6eda3a5e2973f20f82dded8cf8ca196
- Full Text :
- https://doi.org/10.3390/ijms23169403