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Neurodegenerative changes initiated by presynaptic dysfunction.

Yasuda T, Nakata Y, Choong CJ, Mochizuki H - Transl Neurodegener (2013)

Bottom Line: Recent report showed that more than 90% of αSyn aggregates are present in the form of very small deposits in presynaptic terminals of the affected neurons in DLB.However, the mechanisms responsible for presynaptic accumulation of abnormal αSyn remain unclear.In this article, we review recent findings on the involvement of presynaptic dysfunction in the initiation of neuronal dysfunctional changes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. hmochizuki@neurol.med.osaka-u.ac.jp.

ABSTRACT
α-Synucleinopathies are a subgroup of neurodegenerative diseases including dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Pathologically, these disorders can be characterized by the presence of intraneuronal aggregates composed mainly of α-synuclein (αSyn), which are called Lewy bodies and Lewy neurites. Recent report showed that more than 90% of αSyn aggregates are present in the form of very small deposits in presynaptic terminals of the affected neurons in DLB. However, the mechanisms responsible for presynaptic accumulation of abnormal αSyn remain unclear. In this article, we review recent findings on the involvement of presynaptic dysfunction in the initiation of neuronal dysfunctional changes. This review highlights that the presynaptic failure can be a potential trigger of the dying-back neuronal death in neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus

A hypothetical diagram showing enlarged presynaptic nerve terminals in SNAP-25 mutant mice. Normal presynaptic nerve terminals with uniform distribution of vesicles were observed in wild type mice while abnormally enlarged presynaptic nerve terminals with condensed synaptic vesicles and predominant localization of αSyn proteins in the periactive zones were found in SNAP-25 mutant mice, suggesting that SNARE dysfunction leads to presynaptic accumulation of endogenous αSyn and perturbations to the finely-tuned balance between exocytosis and endocytosis.
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Figure 1: A hypothetical diagram showing enlarged presynaptic nerve terminals in SNAP-25 mutant mice. Normal presynaptic nerve terminals with uniform distribution of vesicles were observed in wild type mice while abnormally enlarged presynaptic nerve terminals with condensed synaptic vesicles and predominant localization of αSyn proteins in the periactive zones were found in SNAP-25 mutant mice, suggesting that SNARE dysfunction leads to presynaptic accumulation of endogenous αSyn and perturbations to the finely-tuned balance between exocytosis and endocytosis.

Mentions: In our recent study, we investigated the effects of SNARE dysfunction on endogenous αSyn using Snap25S187A/S187A mutant mice [19]. These mice have homozygous knock-in gene encoding unphosphorylatable S187A-substituted SNAP-25. Snap25S187A/S187A mutant mice present a concomitant reduction of neurotransmitter release, including serotonin and DA, from the amygdala, and develop convulsive seizures and anxiety-related behavior in general activity and light-and-dark preference tests [20]. We found that the mutant mice displayed a significant age-dependent change in the distribution of αSyn and its Ser129-phosphorylated form in abnormally hypertrophied glutamatergic nerve terminals in the striatum. Electron microscopic analysis revealed the atypically condensed synaptic vesicles with concomitant mislocalization of αSyn protein to the periactive zone in the glutamatergic nerve terminals (Figure 1). However, the Snap25S187A/S187A mutant mice harbored no abnormalities in the nigrostriatal dopaminergic neurons [19]. Our results suggest that SNARE dysfunction is the initial trigger of mislocalization and accumulation of αSyn, and probably underlies the pathomechanism of α-synucleinopathies.


Neurodegenerative changes initiated by presynaptic dysfunction.

Yasuda T, Nakata Y, Choong CJ, Mochizuki H - Transl Neurodegener (2013)

A hypothetical diagram showing enlarged presynaptic nerve terminals in SNAP-25 mutant mice. Normal presynaptic nerve terminals with uniform distribution of vesicles were observed in wild type mice while abnormally enlarged presynaptic nerve terminals with condensed synaptic vesicles and predominant localization of αSyn proteins in the periactive zones were found in SNAP-25 mutant mice, suggesting that SNARE dysfunction leads to presynaptic accumulation of endogenous αSyn and perturbations to the finely-tuned balance between exocytosis and endocytosis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3750287&req=5

Figure 1: A hypothetical diagram showing enlarged presynaptic nerve terminals in SNAP-25 mutant mice. Normal presynaptic nerve terminals with uniform distribution of vesicles were observed in wild type mice while abnormally enlarged presynaptic nerve terminals with condensed synaptic vesicles and predominant localization of αSyn proteins in the periactive zones were found in SNAP-25 mutant mice, suggesting that SNARE dysfunction leads to presynaptic accumulation of endogenous αSyn and perturbations to the finely-tuned balance between exocytosis and endocytosis.
Mentions: In our recent study, we investigated the effects of SNARE dysfunction on endogenous αSyn using Snap25S187A/S187A mutant mice [19]. These mice have homozygous knock-in gene encoding unphosphorylatable S187A-substituted SNAP-25. Snap25S187A/S187A mutant mice present a concomitant reduction of neurotransmitter release, including serotonin and DA, from the amygdala, and develop convulsive seizures and anxiety-related behavior in general activity and light-and-dark preference tests [20]. We found that the mutant mice displayed a significant age-dependent change in the distribution of αSyn and its Ser129-phosphorylated form in abnormally hypertrophied glutamatergic nerve terminals in the striatum. Electron microscopic analysis revealed the atypically condensed synaptic vesicles with concomitant mislocalization of αSyn protein to the periactive zone in the glutamatergic nerve terminals (Figure 1). However, the Snap25S187A/S187A mutant mice harbored no abnormalities in the nigrostriatal dopaminergic neurons [19]. Our results suggest that SNARE dysfunction is the initial trigger of mislocalization and accumulation of αSyn, and probably underlies the pathomechanism of α-synucleinopathies.

Bottom Line: Recent report showed that more than 90% of αSyn aggregates are present in the form of very small deposits in presynaptic terminals of the affected neurons in DLB.However, the mechanisms responsible for presynaptic accumulation of abnormal αSyn remain unclear.In this article, we review recent findings on the involvement of presynaptic dysfunction in the initiation of neuronal dysfunctional changes.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Neurology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. hmochizuki@neurol.med.osaka-u.ac.jp.

ABSTRACT
α-Synucleinopathies are a subgroup of neurodegenerative diseases including dementia with Lewy bodies (DLB) and Parkinson's disease (PD). Pathologically, these disorders can be characterized by the presence of intraneuronal aggregates composed mainly of α-synuclein (αSyn), which are called Lewy bodies and Lewy neurites. Recent report showed that more than 90% of αSyn aggregates are present in the form of very small deposits in presynaptic terminals of the affected neurons in DLB. However, the mechanisms responsible for presynaptic accumulation of abnormal αSyn remain unclear. In this article, we review recent findings on the involvement of presynaptic dysfunction in the initiation of neuronal dysfunctional changes. This review highlights that the presynaptic failure can be a potential trigger of the dying-back neuronal death in neurodegenerative diseases.

No MeSH data available.


Related in: MedlinePlus