Dataset Information

The Association between α-Synuclein and α-Tubulin in Brain Synapses.

ABSTRACT: α-synuclein is a small protein that is mainly expressed in the synaptic terminals of nervous tissue. Although its implication in neurodegeneration is well established, the physiological role of α-synuclein remains elusive. Given its involvement in the modulation of synaptic transmission and the emerging role of microtubules at the synapse, the current study aimed at investigating whether α-synuclein becomes involved with this cytoskeletal component at the presynapse. We first analyzed the expression of α-synuclein and its colocalization with α-tubulin in murine brain. Differences were found between cortical and striatal/midbrain areas, with substantia nigra pars compacta and corpus striatum showing the lowest levels of colocalization. Using a proximity ligation assay, we revealed the direct interaction of α-synuclein with α-tubulin in murine and in human brain. Finally, the previously unexplored interaction of the two proteins in vivo at the synapse was disclosed in murine striatal presynaptic boutons through multiple approaches, from confocal spinning disk to electron microscopy. Collectively, our data strongly suggest that the association with tubulin/microtubules might actually be an important physiological function for α-synuclein in the synapse, thus suggesting its potential role in a neuropathological context.

SUBMITTER: Amadeo A

PROVIDER: S-EPMC8430732 | biostudies-literature | 2021 Aug

REPOSITORIES: biostudies-literature

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The Association between α-Synuclein and α-Tubulin in Brain Synapses.

Amadeo Alida A Pizzi Sara S Comincini Alessandro A Modena Debora D Calogero Alessandra Maria AM Madaschi Laura L Faustini Gaia G Rolando Chiara C Bellucci Arianna A Pezzoli Gianni G Mazzetti Samanta S Cappelletti Graziella G

International journal of molecular sciences 20210825 17

α-synuclein is a small protein that is mainly expressed in the synaptic terminals of nervous tissue. Although its implication in neurodegeneration is well established, the physiological role of α-synuclein remains elusive. Given its involvement in the modulation of synaptic transmission and the emerging role of microtubules at the synapse, the current study aimed at investigating whether α-synuclein becomes involved with this cytoskeletal component at the presynapse. We first analyzed the expres ...[more]

PMID: 34502063

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Project description:Importance. Biological markers of Parkinson’s disease are essential for achieving disease modification. Objective. To determine the association of SNCA blood transcript levels with prevalence of Parkinson’s disease. Background. The SNCA locus is preferentially transcribed in neurons and blood cells. Non-coding genetic variants and neuronal aggregates of α-synuclein protein associate this locus with sporadic Parkinson’s disease and suggest a potential role for abnormal SNCA transcription in the disease mechanism. Here we investigated variation in intracellular SNCA gene expression and SNCA transcript isoform abundance in circulating blood cells of cases with PD and controls in a network of biobanks that represent regional, national, and international populations. Design, Setting, Participants. Three cross-sectional, case-control studies nested in observational biomarker studies. 222 cases with early-stage clinical PD and 183 controls were enrolled from 2005 to 2010 in the Harvard Biomarker Study (HBS) at two Harvard-affiliated tertiary care centers. 76 cases with dopamine transporter imaging (DAT)-confirmed PD and 42 controls were enrolled between August 2007 and December 2008 in the Blood α-Synuclein, Gene Expression and Smell Testing as Diagnostic and Prognostic Biomarkers in Parkinson’s Disease Study (PROBE) study from 22 US tertiary care centers. 202 DAT-confirmed cases with de novo PD and 138 controls were enrolled in the Parkinson’s Progression Markers Initiative (PPMI) between July 2010 and November 2012 from 22 US and international tertiary care centers. Main Outcome Measures. Association of intracellular SNCA transcript abundance with PD estimated on analog and digital expression platforms. Results. Reduced levels of SNCA transcripts were associated with early-stage clinical PD, neuroimaging-confirmed PD, and untreated, neuroimaging-confirmed PD in accessible, peripheral blood cells from a total of 863 individuals. SNCA expression was reduced by 17%, 22%, and 16% in cases compared to controls in the HBS, PROBE, and PPMI study with P values of 0.004, 0.025, and 0.018, respectively, after adjusting for clinical, hematological, and processing covariates. Specific SNCA transcripts with long 3’ untranslated regions (UTR) and those skipping exon 5 are implicated in the accumulation and mitochondrial targeting of α-synuclein protein in Parkinson’s pathology. These transcript isoforms were linked to PD through digital expression analysis. Individuals in the lowest quartile of SNCA expression values had covariate-adjusted odds ratios for PD of 2.14 (95% C. I. 1.1-4.1), 4.5 (95% C. I. 1.3-15), and 2.1 (1.1-4.0) compared to individuals in the highest quartile of expression values in the HBS, PROBE, and PPMI study, respectively. Conclusions and Relevance. Reduced levels of SNCA expression, particularly of disease-relevant transcripts with extended 3’ UTR or exon 5 skipping, are associated with early-stage PD. These findings support a potential role for SNCA as a transcriptional marker of PD and may have implications for patient stratification and risk assessment.

Project description:IntroductionOligomeric and fibrillar species of the synaptic protein α-synuclein are established key players in the pathophysiology of Parkinson's disease and other synucleinopathies. Increasing evidence in the literature points to prefibrillar oligomers as the main cytotoxic species driving dysfunction in diverse neurotransmitter systems even at early disease stages. Of note, soluble oligomers have recently been shown to alter synaptic plasticity mechanisms at the glutamatergic cortico-striatal synapse. However, the molecular and morphological detrimental events triggered by soluble α-synuclein aggregates that ultimately lead to excitatory synaptic failure remain mostly elusive.MethodsIn the present study, we aimed to clarify the effects of soluble α-synuclein oligomers (sOligo) in the pathophysiology of synucleinopathies at cortico-striatal and hippocampal excitatory synapses. To investigate early defects of the striatal synapse in vivo, sOligo were inoculated in the dorsolateral striatum of 2-month-old wild-type C57BL/6J mice, and molecular and morphological analyses were conducted 42 and 84 days post-injection. In parallel, primary cultures of rat hippocampal neurons were exposed to sOligo, and molecular and morphological analyses were performed after 7 days of treatment.ResultsIn vivo sOligo injection impaired the post-synaptic retention of striatal ionotropic glutamate receptors and decreased the levels of phosphorylated ERK at 84 days post-injection. These events were not correlated with morphological alterations at dendritic spines. Conversely, chronic in vitro administration of sOligo caused a significant decrease in ERK phosphorylation but did not significantly alter post-synaptic levels of ionotropic glutamate receptors or spine density in primary hippocampal neurons.ConclusionOverall, our data indicate that sOligo are involved in pathogenic molecular changes at the striatal glutamatergic synapse, confirming the detrimental effect of these species in an in vivo synucleinopathy model. Moreover, sOligo affects the ERK signaling pathway similarly in hippocampal and striatal neurons, possibly representing an early mechanism that anticipates synaptic loss.

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Dataset Information

The Association between α-Synuclein and α-Tubulin in Brain Synapses.

Publications

The Association between α-Synuclein and α-Tubulin in Brain Synapses.

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