Mechanisms of Neuronal Death in Synucleinopathy

Takeda, Atsushi; Hasegawa, Takafumi; Matsuzaki-Kobayashi, Michiko; Sugeno, Naoto; Kikuchi, Akio; Itoyama, Yasuto; Furukawa, Koichi

doi:10.1155/jbb/2006/19365

Cited by 30 publications

(18 citation statements)

References 38 publications

(42 reference statements)

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“…Thus, these data suggested that the serine 129 phosphorylation was required not only for aggregate formation but also for the induction of ␣-synuclein toxicity. Because the toxic effect of ␣-synuclein was suggested to be associated with intermediate oligomer formation, so-called protofibrils (23,45), the phosphorylation of ␣-synuclein at serine 129 may be important for the formation of protofibrils. A recent study using NMR also suggested that serine 129 phosphorylation may destabilize the intramolecular interactions, converting ␣-synuclein into more unfolded forms that self-associated readily (46).…”

Section: Discussionmentioning

confidence: 99%

Serine 129 Phosphorylation of α-Synuclein Induces Unfolded Protein Response-mediated Cell Death

Sugeno

Takeda

Hasegawa

et al. 2008

Journal of Biological Chemistry

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131

104

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␣-Synuclein is a major protein component deposited in Lewy bodies and Lewy neurites that is extensively phosphorylated at Ser 129, although its role in neuronal degeneration is still elusive. In this study, several apoptotic pathways were examined in ␣-synuclein-overexpressing SH-SY5Y cells. Following the treatment with rotenone, a mitochondrial complex I inhibitor, wild type ␣-synuclein-overexpressing cells demonstrated intracellular aggregations, which shared a number of features with Lewy bodies, although cells overexpressing the S129A mutant, in which phosphorylation at Ser 129 was blocked, showed few aggregations. In wild type ␣-synuclein cells treated with rotenone, the proportion of phosphorylated ␣-synuclein was about 1.6 times higher than that of untreated cells. Moreover, induction of unfolded protein response (UPR) markers was evident several hours before the induction of mitochondrial disruption and caspase-3 activation. Eukaryotic initiation factor 2␣, a member of the PERK pathway family, was remarkably activated at early phases. On the other hand, the S129A mutant failed to activate UPR. Casein kinase 2 inhibitor, which decreased ␣-synuclein phosphorylation, also reduced UPR activation. The ␣-synuclein aggregations were colocalized with a marker for the endoplasmic reticulum-Golgi intermediate compartment. Taken together, it seems plausible that ␣-synuclein toxicity is dependent on the phosphorylation at Ser 129 that induces the UPRs, possibly triggered by the disturbed endoplasmic reticulum-Golgi trafficking.

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Section: Discussionmentioning

confidence: 99%

Serine 129 Phosphorylation of α-Synuclein Induces Unfolded Protein Response-mediated Cell Death

Sugeno

Takeda

Hasegawa

et al. 2008

Journal of Biological Chemistry

Self Cite

131

104

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“…including oxidative stress (Hasegawa et al 2003(Hasegawa et al , 2007Hasegawa 2010), endoplasmic reticulum stress (Sugeno et al 2008;Mercado et al 2016), mitochondrial dysfunction (Mizuno et al 1998;Rothfuss et al 2009), misfolded protein toxicity Takeda et al 2006), ubiquitin-proteasome dysfunction Vilchez et al 2014;Matsuda 2016), neuroinflammation , impairment of the autophagy-lysosome system (Ferrucci et al 2008;Oshima et al 2016), and alterations in the membrane trafficking pathway (Abeliovich and Gitler 2016). Among them, recent advances in clinical genetics and studies using model organisms have emphasized that the membrane trafficking pathway contributes immensely to the pathogenesis of PD and related neurodegenerative disorders.…”

Section: Introductionmentioning

confidence: 99%

Membrane Trafficking Illuminates a Path to Parkinson’s Disease

Hasegawa

Sugeno

Kikuchi

et al. 2017

Tohoku J. Exp. Med.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder that is characterized by progressive movement disability and a variety of non-motor symptoms. The neuropathology of PD consists of the loss of dopaminergic neurons in the midbrain and the appearance of neuronal inclusions called Lewy bodies, which contain insoluble α-synuclein, a relatively small protein originally identified in association with synaptic vesicles in the presynaptic nerve terminals. Drugs that replenish dopamine can partly alleviate the motor symptoms, but they do not cure the disease itself. Therefore, there is an urgent need for disease modification in terms of the delay or prevention of neurodegeneration. Recent advances in genetic and biochemical studies have provided unifying conceptual frameworks of the pathogenesis of PD. Particularly, membrane trafficking has aroused special attention as an initiator or enhancer of the neurodegenerative process that leads to PD. Defects in the cellular trafficking pathway result in synaptic dysfunction and the accumulation of misfolded α -synuclein. Likewise, changes in intracellular sorting and degradation profoundly influence the cellular trafficking of misfolded proteins, thereby facilitating the cell-to-cell spreading of hazardous α-synuclein species in a prion-like manner. Here, we will review our current knowledge of the functional roles of membrane trafficking in PD and will discuss how this cellular process could induce or facilitate the functional and pathological alterations in this disease.

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“…Interestingly, this effect was increased by the familial PD-linked mutants A30P and A53T [216] but not by the mutant E46K [217]. Thus, although pore formation may be involved insynuclein-induced toxicity, other mechanisms also have been implicated, but these are not well understood [218].…”

Section: Oligomers Of Disease-related Amyloido-genic Proteins Other Tmentioning

confidence: 99%

Structure – Function Relationships of Pre-Fibrillar Protein Assemblies in Alzheimers Disease and Related Disorders

Rahimi

Shanmugam²,

Bitan³

2008

CAR

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Several neurodegenerative diseases, including Alzheimer's, Parkinson's, Huntington's and prion diseases, are characterized pathognomonically by the presence of intra- and/or extracellular lesions containing proteinaceous aggregates, and by extensive neuronal loss in selective brain regions. Related non-neuropathic systemic diseases, e.g., light-chain and senile systemic amyloidoses, and other organ-specific diseases, such as dialysis-related amyloidosis and type-2 diabetes mellitus, also are characterized by deposition of aberrantly folded, insoluble proteins. It is debated whether the hallmark pathologic lesions are causative. Substantial evidence suggests that these aggregates are the end state of aberrant protein folding whereas the actual culprits likely are transient, pre-fibrillar assemblies preceding the aggregates. In the context of neurodegenerative amyloidoses, the proteinaceous aggregates may eventuate as potentially neuroprotective sinks for the neurotoxic, oligomeric protein assemblies. The pre-fibrillar, oligomeric assemblies are believed to initiate the pathogenic mechanisms that lead to synaptic dysfunction, neuronal loss, and disease-specific regional brain atrophy. The amyloid beta-protein (Abeta), which is believed to cause Alzheimer's disease (AD), is considered an archetypal amyloidogenic protein. Intense studies have led to nominal, functional, and structural descriptions of oligomeric Abeta assemblies. However, the dynamic and metastable nature of Abeta oligomers renders their study difficult. Different results generated using different methodologies under different experimental settings further complicate this complex area of research and identification of the exact pathogenic assemblies in vivo seems daunting. Here we review structural, functional, and biological experiments used to produce and study pre-fibrillar Abeta assemblies, and highlight similar studies of proteins involved in related diseases. We discuss challenges that contemporary researchers are facing and future research prospects in this demanding yet highly important field.

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Mechanisms of Neuronal Death in Synucleinopathy

Cited by 30 publications

References 38 publications

Serine 129 Phosphorylation of α-Synuclein Induces Unfolded Protein Response-mediated Cell Death

Serine 129 Phosphorylation of α-Synuclein Induces Unfolded Protein Response-mediated Cell Death

Membrane Trafficking Illuminates a Path to Parkinson’s Disease

Structure – Function Relationships of Pre-Fibrillar Protein Assemblies in Alzheimers Disease and Related Disorders

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