SAK3 Administration Improves Spine Abnormalities and Cognitive Deficits in AppNL-G-F/NL-G-F Knock-in Mice by Increasing Proteasome Activity through CaMKII/Rpt6 Signaling

Alzheimer’s disease (AD) is the most common form of dementia and is characterized by neuropathological hallmarks consisting of accumulation of extracellular amyloid-β (Aβ) plaques and intracellular neurofibrillary tangles (NFT). Recently, we have identified a new AD therapeutic candidate, ethyl-8′-methyl-2′,4-dioxo-2-(piperidin-1-yl)-2′H-spiro[cyclopentane-1,3′-imidazo [1,2-a] pyridin]-2-ene-3-carboxylate (SAK3), which ameliorates the AD-like pathology in AppNL-F/NL-F knock-in mice. However, the detailed mechanism underlying the therapeutic effects of SAK3 remains unclear. In this study, we found that SAK3 administration improved the reduced proteasome activity through the activation of CaMKII/Rpt6 signaling in AppNL-F/NL-F knock-in (NL-G-F) mice. Moreover, spine abnormalities observed in NL-G-F mice were significantly reversed by SAK3 administration. Along with this, cognitive impairments found in NL-G-F mice were markedly ameliorated by SAK3. In summary, our data suggest that SAK3 administration increases the activity of the proteasome via activation of the CaMKII/Rpt6 signaling pathway, contributing to improvements in spine abnormalities and cognitive deficits in NL-G-F mice. Overall, our findings suggest that SAK3 might be a new attractive drug candidate, representing a new mechanism for the treatment of AD pathology

An α-synuclein decoy peptide prevents cytotoxic α-synuclein aggregation caused by fatty acid binding protein 3

α-synuclein (αSyn) is a protein known to form intracellular aggregates during the manifestation of Parkinson’s disease. Previously, it was shown that αSyn aggregation was strongly suppressed in the midbrain region of mice that did not possess the gene encoding the lipid transport protein fatty acid binding protein 3 (FABP3). An interaction between these two proteins was detected in vitro, suggesting that FABP3 may play a role in the aggregation and deposition of αSyn in neurons. In order to characterize the molecular mechanisms that underlie the interactions between FABP3 and αSyn that modulate the cellular accumulation of the latter, in this report, we used in vitro fluorescence assays combined with fluorescence microscopy, transmission electron microscopy, and quartz crystal microbalance assays to characterize in detail the process and consequences of FABP3-αSyn interaction. We demonstrated that binding of FABP3 to αSyn results in changes in the aggregation mechanism of the latter; specifically, a suppression of fibrillar forms of αSyn, and also the production of aggregates with an enhanced cytotoxicity toward mice neuro2A cells. Since this interaction involved the C-terminal sequence region of αSyn, we tested a peptide derived from this region of αSyn (αSynP130-140) as a decoy to prevent the FABP3-αSyn interaction. We observed that the peptide competitively inhibited binding of αSyn to FABP3 in vitro and in cultured cells. We propose that administration of αSynP130-140 might be used to prevent the accumulation of toxic FABP3-αSyn oligomers in cells, thereby preventing the progression of Parkinson’s disease

Two Distinct Mechanisms for Actin Capping Protein Regulation—Steric and Allosteric Inhibition

A crystallographic study reveals the structural basis for regulation by two different inhibitors of the actin capping protein, a critical factor controlling actin-driven cell motility

Fatty Acid Binding Protein 5 Mediates Cell Death by Psychosine Exposure through Mitochondrial Macropores Formation in Oligodendrocytes

Oligodendrocytes, the myelinating cells in the central nervous system (CNS), are critical for producing myelin throughout the CNS. The loss of oligodendrocytes is associated with multiple neurodegenerative disorders mediated by psychosine. However, the involvement of psychosine in the critical biochemical pathogenetic mechanism of the loss of oligodendrocytes and myelin in krabbe disease (KD) remains unclear. Here, we addressed how oligodendrocytes are induced by psychosine treatment in both KG-1C human oligodendroglial cells and mouse oligodendrocyte precursor cells. We found that fatty acid binding protein 5 (FABP5) expressed in oligodendrocytes accelerates mitochondria-induced glial death by inducing mitochondrial macropore formation through voltage-dependent anion channels (VDAC-1) and BAX. These two proteins mediate mitochondrial outer membrane permeabilization, thereby leading to the release of mitochondrial DNA and cytochrome C into the cytosol, and the activation of apoptotic caspases. Furthermore, we confirmed that the inhibition of FABP5 functions by shRNA and FABP5-specific ligands blocking mitochondrial macropore formation, thereby rescuing psychosine-induced oligodendrocyte death. Taken together, we identified FABP5 as a critical factor in mitochondrial injury associated with psychosine-induced apoptosis in oligodendrocytes

Pathogenic Impact of α-Synuclein Phosphorylation and Its Kinases in α-Synucleinopathies

α-Synuclein is a protein with a molecular weight of 14.5 kDa and consists of 140 amino acids encoded by the SNCA gene. Missense mutations and gene duplications in the SNCA gene cause hereditary Parkinson’s disease. Highly phosphorylated and abnormally aggregated α-synuclein is a major component of Lewy bodies found in neuronal cells of patients with sporadic Parkinson’s disease, dementia with Lewy bodies, and glial cytoplasmic inclusion bodies in oligodendrocytes with multiple system atrophy. Aggregated α-synuclein is cytotoxic and plays a central role in the pathogenesis of the above-mentioned synucleinopathies. In a healthy brain, most α-synuclein is unphosphorylated; however, more than 90% of abnormally aggregated α-synuclein in Lewy bodies of patients with Parkinson’s disease is phosphorylated at Ser129, which is presumed to be of pathological significance. Several kinases catalyze Ser129 phosphorylation, but the role of phosphorylation enzymes in disease pathogenesis and their relationship to cellular toxicity from phosphorylation are not fully understood in α-synucleinopathy. Consequently, this review focuses on the pathogenic impact of α-synuclein phosphorylation and its kinases during the neurodegeneration process in α-synucleinopathy

Fatty Acid-Binding Protein 3 is Critical for α-Synuclein Uptake and MPP+-Induced Mitochondrial Dysfunction in Cultured Dopaminergic Neurons

International audienceα-Synuclein is an abundant neuronal protein that accumulates in insoluble inclusions in Parkinson s disease and other synucleinopathies. Fatty acids partially regulate α-Synuclein accumulation, and mesencephalic dopaminergic neurons highly express fatty acid-binding protein 3 (FABP3). We previously demonstrated that FABP3 knockout mice show decreased α-Synuclein oligomerization and neuronal degeneration of tyrosine hydroxylase (TH)-positive neurons in vivo. In this study, we newly investigated the importance of FABP3 in α-Synuclein uptake, 1-methyl-4-phenylpyridinium (MPP +)-induced axodendritic retraction, and mitochondrial dysfunction. To disclose the issues, we employed cultured mesencephalic neurons derived from wild type or FABP3 −/− C57BL6 mice and performed immunocytochemical analysis. We demonstrated that TH + neurons from FABP3 +/+ mice take up α-Synuclein monomers while FABP3 −/− TH + neurons do not. The formation of filamentous α-Synuclein inclusions following treatment with MPP + was observed only in FABP3 +/+ , and not in FABP3 −/− neurons. Notably, detailed morphological analysis revealed that FABP −/− neurons did not exhibit MPP +-induced axodendritic retraction. Moreover, FABP3 was also critical for MPP +-induced reduction of mitochondrial activity and the production of reactive oxygen species. These data indicate that FABP3 is critical for α-Synuclein uptake in dopaminergic neurons, thereby preventing synucleinopathies, including Parkinson s disease

Impact of Fatty Acid-Binding Proteins in α-Synuclein-Induced Mitochondrial Injury in Synucleinopathy

Synucleinopathies are diverse diseases with motor and cognitive dysfunction due to progressive neuronal loss or demyelination, due to oligodendrocyte loss in the brain. While the etiology of neurodegenerative disorders (NDDs) is likely multifactorial, mitochondrial injury is one of the most vital factors in neuronal loss and oligodendrocyte dysfunction, especially in Parkinson’s disease, dementia with Lewy body, multiple system atrophy, and Krabbe disease. In recent years, the abnormal accumulation of highly neurotoxic α-synuclein in the mitochondrial membrane, which leads to mitochondrial dysfunction, was well studied. Furthermore, fatty acid-binding proteins (FABPs), which are members of a superfamily and are essential in fatty acid trafficking, were reported to trigger α-synuclein oligomerization in neurons and glial cells and to target the mitochondrial outer membrane, thereby causing mitochondrial loss. Here, we provide an updated overview of recent findings on FABP and α-synuclein interactions and mitochondrial injury in NDDs