A Lipophilic 4‐Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins

Azoulay-Ginsburg, Salome; Trobiani, Laura; Setini, Andrea; Favaloro, Flores Lietta; Giorda, Ezio; Jacob, Avi; Hauschner, Hagit; Levy, Laura M.; Cestra, Gianluca; Jaco, Antonella De; Gruzman, Arie

doi:10.1002/chem.201904292

Cited by 11 publications

(20 citation statements)

References 42 publications

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“…One such compound is the FDA-approved drug 4-phenylbutyric acid (4-PBA). Yet, due to the barely tolerated high doses required, and considering that ALS is a chronic disease, the use of 4-PBA is not a realistic treatment option [ 355 ]. However, 4-PBA derivatives targeted to the lysosome or the ER reduce the effective concentration needed for the therapeutic effect and showed a beneficial effect in C9orf72 Drosophila model [ 356 ].…”

Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

Argueti-Ostrovsky

Alfahel

Kahn

et al. 2021

Cells

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Multiple neurodegenerative diseases (NDDs) such as Alzheimer’s disease (AD), Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington’s disease (HD) are being suggested to have common cellular and molecular pathological mechanisms, characterized mainly by protein misfolding and aggregation. These large inclusions, most likely, represent an end stage of a molecular cascade; however, the soluble misfolded proteins, which take part in earlier steps of this cascade, are the more toxic players. These pathological proteins, which characterize each specific disease, lead to the selective vulnerability of different neurons, likely resulting from a combination of different intracellular mechanisms, including mitochondrial dysfunction, ER stress, proteasome inhibition, excitotoxicity, oxidative damage, defects in nucleocytoplasmic transport, defective axonal transport and neuroinflammation. Damage within these neurons is enhanced by damage from the nonneuronal cells, via inflammatory processes that accelerate the progression of these diseases. In this review, while acknowledging the hallmark proteins which characterize the most common NDDs; we place specific focus on the common overlapping mechanisms leading to disease pathology despite these different molecular players and discuss how this convergence may occur, with the ultimate hope that therapies effective in one disease may successfully translate to another.

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Section: Amyotrophic Lateral Sclerosismentioning

confidence: 99%

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

Argueti-Ostrovsky

Alfahel

Kahn

et al. 2021

Cells

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“…The Arg residue at position 451 in NLGN3 is highly conserved among cholinesterase-like proteins (De Jaco et al, 2012. The R451C substitution impairs NLGN3 folding and/or dimerization and trafficking to the cell surface, causing retention in the ER and degradation via the proteasome (Azoulay-Ginsburg et al, 2020;De Jaco et al, 2010.…”

Section: Neuroligin3mentioning

confidence: 99%

The neuroligins and the synaptic pathway in Autism Spectrum Disorder

Trobiani

Meringolo

Diamanti

et al. 2020

Neuroscience & Biobehavioral Reviews

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HAL is a multi-disciplinary open access archive for the deposit and dissemination of scientific research documents, whether they are published or not. The documents may come from teaching and research institutions in France or abroad, or from public or private research centers. L'archive ouverte pluridisciplinaire HAL, est destinée au dépôt et à la diffusion de documents scientifiques de niveau recherche, publiés ou non, émanant des établissements d'enseignement et de recherche français ou étrangers, des laboratoires publics ou privés.

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“…Moreover, 4-PBA was also shown to have a potential therapeutic effect in several mouse models of other neurodegenerative disorders, also characterized by protein aggregation, such as Alzheimer’s disease [ 31 ] and Huntington’s disease [ 32 ]. Despite these accumulating findings, suggesting a positive effect of 4-PBA treatment, the main drawback to its therapeutic use is the high dosage required—0.5 to 20 g per kg per day [ 30 ], a nonrealistic dosage for treating chronic disorders such as ALS [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, Azoulay-Ginsburg S. and colleagues identified and synthesized 4-PBA derivatives in order to reduce the effective concentration required to achieve a therapeutic effect. Two 4-PBA derivatives, N -(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenylbutanamide (compound 4 , C4) and 2-isopropyl-4-phenylbutanoic acid (compound 5 , C5) ( Figure 1 ), exhibited positive outcomes when tested in several in vitro and in vivo models of neurodegenerative diseases, characterized by protein aggregation [ 33 , 34 ]. More specifically, compared to 4-PBA, the identified chemical chaperone C5 was more effective in protecting cells under ER stress conditions in vitro.…”

Section: Introductionmentioning

confidence: 99%

“…More specifically, compared to 4-PBA, the identified chemical chaperone C5 was more effective in protecting cells under ER stress conditions in vitro. C5 also reduced the secretion rate of mutant Neuroligin3 (an autism-related protein), acted as a direct chemical chaperone for purified proteins, and reduced protein aggregation in the PC12 neuronal cell model [ 33 ]. The other chemical chaperone synthesized, C4, was selectively targeted to the lysosome, part of the cell clearance system, which may increase its effectivity and reduce its effective therapeutic concentration.…”

Section: Introductionmentioning

confidence: 99%

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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

Alfahel

Argueti-Ostrovsky

Barel

et al. 2022

IJMS

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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.

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A Lipophilic 4‐Phenylbutyric Acid Derivative That Prevents Aggregation and Retention of Misfolded Proteins

Cited by 11 publications

References 42 publications

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

All Roads Lead to Rome: Different Molecular Players Converge to Common Toxic Pathways in Neurodegeneration

The neuroligins and the synaptic pathway in Autism Spectrum Disorder

4-Phenylbutyric Acid (4-PBA) Derivatives Prevent SOD1 Amyloid Aggregation In Vitro with No Effect on Disease Progression in SOD1-ALS Mice

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