TY - JOUR
T1 - 4-Phenylbutyric Acid (4-PBA) Derivatives Prevent SOD1 Amyloid Aggregation In Vitro with No Effect on Disease Progression in SOD1-ALS Mice
AU - Alfahel, Leenor
AU - Argueti-Ostrovsky, Shirel
AU - Barel, Shir
AU - Ali Saleh, Mahmood
AU - Kahn, Joy
AU - Azoulay-Ginsburg, Salome
AU - Rothstein, Ayelet
AU - Ebbinghaus, Simon
AU - Gruzman, Arie
AU - Israelson, Adrian
N1 - Funding Information: This work was funded by a grant from the German–Israeli Foundation (GIF# I-5-201.6-2016) to A.G., S.E., and A.I., and a grant from the Israeli Science Foundation (ISF# 284/19) to A.I. Publisher Copyright: © 2022 by the authors.
PY - 2022/8/20
Y1 - 2022/8/20
N2 - 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.
AB - 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.
KW - aggregation
KW - amyotrophic lateral sclerosis (ALS)
KW - chemical chaperones
KW - misfolded proteins
KW - mutant SOD1
UR - http://www.scopus.com/inward/record.url?scp=85137126247&partnerID=8YFLogxK
U2 - 10.3390/ijms23169403
DO - 10.3390/ijms23169403
M3 - Article
C2 - 36012668
SN - 1661-6596
VL - 23
JO - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
IS - 16
M1 - 9403
ER -