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

Fukui, Naoya; Yamamoto, Hideki; Miyabe, Moe; Aoyama, Yuki; Hongo, Kunihiro; Mizobata, Tomohiro; Kawahata, Ichiro; Yabuki, Yasushi; Shinoda, Yasuharu; Fukunaga, Kohji; Kawata, Yasushi

doi:10.1016/j.jbc.2021.100663

Cited by 13 publications

(23 citation statements)

References 61 publications

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“…In addition, α-synuclein is observed in the mitochondrial inner membrane, the mitochondria-associated endoplasmic reticulum membranes, the Golgi apparatus, and endosomes [ 6 , 7 , 8 , 9 ]. It also interacts with various proteins, including tau, ATPases, lipid membranes, lymphocyte-activation gene 3, flotillin, and fatty acid-binding protein 3 [ 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ], as well as metal ions [ 21 , 22 ]. Nuclear α-synuclein presumably functions as a DNA-binding protein and is thought to be involved in regulating various gene expressions [ 23 , 24 , 25 ].…”

Section: Characteristics and Distribution Of α-Synucleinmentioning

confidence: 99%

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

Kawahata

Finkelstein

Fukunaga

2022

IJMS

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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.

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Section: Characteristics and Distribution Of α-Synucleinmentioning

confidence: 99%

“…The carboxy-terminal region of α-synuclein is flexible in monomeric and fibrillar forms as well as in membrane-bound states [ 4 , 18 , 51 , 52 , 53 ]. Interestingly, the α-synuclein C-terminal tail contains the majority of phosphorylation sites ( Figure 3 ).…”

Section: Kinases That Phosphorylate α-Synuclein and Their Association...mentioning

confidence: 99%

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

Kawahata

Finkelstein

Fukunaga

2022

IJMS

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“…Moreover, FABP3-mediated AA incorporation following neurotoxin exposure induces α-synuclein oligomerization. Importantly, α-synuclein binds to FABP3 directly via its C-terminal region and enhances the formation of toxic oligomers (Figure 3) [116]. Additionally, inhibition of FABP3 by FABP3 ligands also significantly attenuated α-synuclein oligomerization [117], dopamine neuronal loss, and behavioral impairments [118].…”

Section: Fabp3 In α-Synuclein Oligomerization and Migrationmentioning

confidence: 99%

“…However, in the presence of FABP3, α-synuclein binds to FABP3 via its C-terminal region and forms a soluble α-synuclein-FABP3 (1:1) complex. In addtion, the α-synuclein-FABP3 complex changes over time to oligomeric forms, (α-synuclein-FABP3)n that displays cytotoxicity (modified from [116]).…”

Section: Fabp3 In α-Synuclein Oligomerization and Migrationmentioning

confidence: 99%

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

et al. 2021

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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.

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“…Impairment of mitochondria can cause brain dysfunction. One of the main causes is the buildup of -synuclein in mitochondria [7,8,9]. This condition can be prevented by the use of H2O2, which in the brain ischaemia model, provides a neuroprotection effect [10,11,12].…”

Section: Introductionmentioning

confidence: 99%

Epigenetics and Dysfunctional Energy Factors of Neurodegenerative Disease with Therapeutic Potential of H<sub>2</sub>O<sub>2</sub> as Neuroprotective Agent

Widyarti¹,

Wibowo²,

Sabarudin³

et al. 2022

Preprint

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The number of people with neurodegenerative disease continues to increase every year. A new perspective is needed in overcoming this disease. In this review, researchers collected information about epigenetics and energy factors of neurodegenerative disease driven by mitochondria. Mitochondrial epigenetic dysregulation can cause damage to the neuron system. The increase in the amount and interaction of alpha-synuclein with SAMM50 in the mitochondria is one of the factors causing neurodegenerative disease. As an energy provider in the body, the existence of harmonization in the regulation of mitochondria specifically the mitochondrial outer membrane is important. Hydrogen peroxide (H2O2) has neuroprotective abilities to overcome the impairment function of mitochondria in neurodegenerative patients. Based on the computational simulation of this case, it can be used as the basic concept for the development of the role of H2O2 in neurodegenerative disease.

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

Cited by 13 publications

References 61 publications

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

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

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

Epigenetics and Dysfunctional Energy Factors of Neurodegenerative Disease with Therapeutic Potential of H<sub>2</sub>O<sub>2</sub> as Neuroprotective Agent

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