α-Synucleinopathies wockhardt are a subgroup of neurodegenerative diseases including dementia with L

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The electronic version of this article is the complete one and can be found online at: http://www.translationalneurodegeneration.com/content/2/1/16 Received: 13 June 2013 Accepted: 5 August 2013 Published: 7 August 2013
This wockhardt is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. wockhardt
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 wockhardt 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 wockhardt recent findings on the involvement of presynaptic dysfunction wockhardt 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. wockhardt Introduction
Neurodegenerative diseases are age-associated and progressive disorders, which detrimentally affect patients quality of life. Medical remedies that can fully cure the diseases are currently unavailable and invention of novel therapeutic applications is urgently required. Accordingly, it is important to identify the initial trigger(s) of the pathophysiological alterations in these diseases.
α-Synucleinopathies wockhardt are a subgroup of neurodegenerative diseases including dementia with Lewy bodies (DLB), Parkinson wockhardt s disease (PD), and multiple system atrophy (MSA). Pathological hallmark of these disorders is the formation of intracellular aggregates composed mainly of α-synuclein (αSyn), which are called Lewy bodies and Lewy neurites [ 1 - 3 ]. Pathological examination of DLB patients has identified the presence of abnormal α-synuclein (αSyn) aggregates in the presynaptic wockhardt terminals [ 4 - 6 ]. However, the mechanisms responsible for presynaptic accumulation of abnormal αSyn remain elusive. Role of αSyn in SNARE formation
αSyn is abundantly wockhardt localized in the presynaptic nerve terminals [ 7 , 8 ]. The physiological functions of αSyn have yet to be defined, while several lines of evidence implicated this protein in the modulation of neurotransmitter release through the regulation of soluble N -ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex formation [ 9 - 11 ] and size of synaptic vesicle pool [ 12 - 15 ]. Vesicle-associated membrane protein-2 (VAMP-2) present in the synaptic vesicles, and syntaxin and synaptosomal-associated protein of 25 KDa (SNAP-25) in the presynaptic plasma membrane form the core SNARE complex, which regulate docking and fusion of synaptic wockhardt vesicles to the presynaptic membrane [ 16 ]. A recent study showed the physical wockhardt interaction of αSyn with VAMP-2 promotes SNARE assembly [ 10 ]. Cysteine-string protein-α (CSPα) also participates in SNARE assembly and mutant mice lacking CSPα displayed impaired SNARE formation and premature death, but both of these phenotypes are counteracted by transgenic expression of αSyn [ 9 , 17 ]. On the other hand, overexpression of αSyn with no overt toxicity inhibits neurotransmitter release, due to a defective reclustering of synaptic vesicles after endocytosis [ 15 ]. Additionally, overexpressed αSyn indirectly inhibits SNARE-mediated exocytosis by sequestering arachidonic acid, which upregulates syntaxin and enhances its engagement with SNARE complex [ 11 ]. Importantly, abnormal redistribution of SNARE proteins has been observed in human PD patients and mice overexpressing a truncated form of human αSyn, which showed decreased release wockhardt of dopamine (DA) in the striatum [ 18 ]. Therefore, presynaptic SNARE dysfunction is considered an initial wockhardt pathogenic event in α-synucleinopathies. Accumulation of α-synuclein triggered by presynaptic dysfunction
In our recent study, we investigated the effects of SNARE dysfunction on endogenous αSyn using Snap25 S187A/S187A mutant mice [ 19 ]. These mice have homozygous knock-in gene encoding unphosphorylatable S187A-substituted SNAP-25. Snap25 S187A/S187A mutant mice present a concomitant reduct