Localization of synucleins in the mammalian cochlea. Akil, O; Weber, CM; Park, SN; Ninkina, N; Buchman, V; Lustig, LR Journal of the Association for Research in Otolaryngology : JARO
9
452-63
2008
Show Abstract
Synucleins are widely expressed synaptic proteins within the central nervous system that have been implicated in such neurodegenerative disorders as Parkinson's disease. In this study, an initial characterization of all three synucleins, alpha-, beta-, and gamma-synuclein, within the cochlea was undertaken. Reverse transcriptase-polymerase chain reaction (PCR) demonstrated all three synuclein mRNA species within microdissected cochlear tissue. Quantitative PCR suggests that beta-synuclein is the most abundantly expressed form, followed by gamma- and then alpha-synuclein. Western blot analysis similarly demonstrates all three synuclein proteins within microdissected cochlear tissue. Immunofluorescence localizes the three synucleins predominantly to the efferent neuronal system at the efferent outer hair cell synapse, with some additional localization within the efferent tunnel-crossing fibers (alpha- and gamma-synuclein), spiral ganglion (beta-synuclein), inner spiral bundle (gamma-synuclein), and stria vascularis (alpha- greater than beta-synuclein). Developmentally, gamma-synuclein can be seen in the region of the outer hair cells by E19, while alpha- and beta-synuclein do not clearly appear there until approximately P10. Additional studies in a null-mutant gamma-synuclein mouse show no histological changes in the organ of Corti with normal hair cell and spiral ganglion cell counts, and normal ABR and DPOAE thresholds in wild-type vs mutant littermates. Together, these results localize synucleins to the efferent cholinergic neuronal auditory system, pointing to a role in normal auditory function, and raising the potential implications for their role in auditory neurodegenerative disorders. However, gamma-synuclein alone is not required for the development and maintenance of normal hearing through P21. Whether overlapping roles of the other synucleins help compensate for the loss of gamma-synuclein remains to be determined. Full Text Article | | 18665422
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Alpha-synuclein: its biological function and role in neurodegenerative diseases. Kaplan, Batia, et al. J. Mol. Neurosci., 20: 83-92 (2003)
2003
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Alpha-synuclein is regarded as a presynaptic protein, which may play an important role in neuronal plasticity. However, the actual physiological function of this protein is not completely clear. Abnormal accumulation of fibrillar alpha-synuclein in Lewy bodies, as well as mutations in the alpha-synuclein gene identified in the familial forms of Parkinson's disease, point to a central role of this protein in the pathophysiology of Lewy body-related disorders. In vivo and in vitro studies showed that overexpression of alpha-synuclein, its aggregation, and interaction with other proteins are the most critical factors affecting the survival of neurons. In Alzheimer's disease, the amount of alpha-synuclein is found to be elevated at synapses, whereas a peptide derived from alpha-synuclein is thought to represent an intrinsic component of amyloid plaques. It is likely that in this disorder alpha-synuclein plays a dual role by being involved not only in synaptic function but also in amyloid beta-fibrillogenesis. | | 12794302
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Oxidative modifications of alpha-synuclein. Ischiropoulos, Harry Ann. N. Y. Acad. Sci., 991: 93-100 (2003)
2003
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Hallmark lesions of neurodegenerative synucleinopathies contain alpha-synuclein (alpha-syn) that is modified by nitration of tyrosine residues and possibly by dityrosine cross-linking to generated stable oligomers. Data gathered from in vitro experiments and from model systems of cells transfected with wild-type and mutant alpha-syn revealed that conditions resulting in alpha-syn nitration also induce formation of alpha-syn inclusions with similar biochemical characteristics to protein extracted from human lesions. The detection of tyrosine-nitrated alpha-syn signifies the formation of reactive nitrogen species capable of both radical and electrophilic attack on aromatic residues as well as nucleophilic additions and oxidations. The cellular sources and biochemical reactivity of reactive nitrogen species in the central nervous system remain largely unknown, but kinetically fast reactions of nitric oxide with superoxide to form peroxynitrite as well as enzymatic one-electron oxidation of nitrite are two important sources of reactive nitrogen species. Based on these findings a model is proposed where the process of fibrilization can be differentially affected by oxidants and nitrating species. Posttranslational modifications of alpha-syn by reactive nitrogen species inhibits fibril formation and results in urea- and SDS- insoluble, protease-resistant alpha-syn aggregates that maybe responsible for cellular toxicity. | | 12846977
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Development of new treatments for Parkinson's disease in transgenic animal models: a role for beta-synuclein. Masliah, Eliezer and Hashimoto, Makoto Neurotoxicology, 23: 461-8 (2002)
2002
Show Abstract
Neuronal death in Parkinson's disease (PD), one of the most common neurodegenerative disorders in the adult and aging population is probably caused by misfolding of synaptic proteins such as alpha-synuclein. Although, some treatments are currently available to control some of the symptoms of PD, none of these approaches directly addresses the mechanisms of disease. With the advent of new experimental animal models for this disorder, the potential for development and discovery of new treatment has been significantly bolstered. Among them, overexpression of alpha-synuclein results in motor deficits. dopaminergic loss and formation of inclusion bodies. Co-expression of mutant amyloid precursor protein, accelerates alpha-synuclein aggregation and enhances the neurodegenerative pathology in these mice, providing a unique model where to investigate the interactions between Abeta1-42 and alpha-synuclein and to develop treatments for combined Alzheimer's disease and PD. Development of anti-parkinsonian treatments based on these models includes: (i) anti-aggregation or pro-degradation compounds, (ii) neuroprotective compounds, and (iii) neurotrophic agents. Among them, we characterized beta-synuclein, the non-amyloidogenic homologue of alpha-synuclein, as an inhibitor of aggregation of alpha-synuclein. Our results raise the intriguing possibility that beta-synuclein might be a natural negative regulator of alpha-synuclein aggregation, and that a similar class of endogenous factors might regulate the aggregation state of other molecules involved in neurodegeneration. Such an anti-amyloidogenic property of beta-synuclein might also provide a novel strategy for the treatment of neurodegenerative disorders. | | 12428718
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A panel of epitope-specific antibodies detects protein domains distributed throughout human alpha-synuclein in Lewy bodies of Parkinson's disease Giasson, B. I., et al J Neurosci Res, 59:528-33 (2000)
2000
| Immunoblotting (Western), Immunohistochemistry (Tissue) | 10679792
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Glial cytoplasmic inclusions in white matter oligodendrocytes of multiple system atrophy brains contain insoluble alpha-synuclein. Tu, P H, et al. Ann. Neurol., 44: 415-22 (1998)
1998
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Recently, alpha-synuclein was shown to be a structural component of the filaments in Lewy bodies (LBs) of Parkinson's disease (PD), dementia with LBs (DLB) as well as the LB variant of Alzheimer's disease, and this suggests that alpha-synuclein could play a mechanistic role in the pathogenesis of these disorders. To determine whether alpha-synuclein is a building block of inclusions in other neurodegenerative movement disorders, we examined brains from patients with multiple system atrophy (MSA) and detected alpha-synuclein, but not beta- or gamma-synuclein, in glial cytoplasmic inclusions (GCIs) throughout the MSA brain. In MSA white matter, alpha-synuclein-positive GCIs were restricted to oligodendrocytes, and alpha-synuclein was localized to the filaments in GCIs by immunoelectron microscopy. Finally, we demonstrated that insoluble alpha-synuclein accumulated selectively in MSA white matter with alpha-synuclein-positive GCIs. Taken together with evidence that LBs contain insoluble alpha-synuclein, our data suggest that a reduction in the solubility of alpha-synuclein may induce this protein to form filaments that aggregate into cytoplasmic inclusions, which contribute to the dysfunction or death of glial cells as well as neurons in neurodegenerative disorders with different phenotypes. | Immunoblotting (Western) | 9749615
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