Low alpha-synuclein 126 mRNA levels in dementia with Lewy bodies and Alzheimer disease

Beyer, Katrin; Humbert, Jordi; Ferrer, Anna Llorens; Lao, José I.; Carrato, Cristina; López, Dolores; Ferrer, Isidró; Ariza, Aurelio

doi:10.1097/01.wnr.0000224773.66904.e7

Cited by 47 publications

(46 citation statements)

References 24 publications

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“…Though accelerated fibrillogenesis and enhanced aggregation was expected with the deletion of the functional domains [10,29], the alternative isoforms actually aggregate less than the canonical isoform SNCA140 [12]. The interruption of the domain responsible for protein-membrane interaction at the protein N-terminus even makes SNCA 126 an aggregation-preventing isoform [28]. In this way, we surmise that transcripts SNCA-007 and SNCA-E3E4, which correlated positively with the monoaminergic neuron function, were neuron protective isoforms.…”

mentioning

confidence: 69%

“…In line with previous reports indicating presynaptic α-synuclein aggregation is involved in synaptic function [25], the current study showed a significant positive correlation between α-synuclein transcripts and cerebral 18 F-AV133 SUVRs. While the biological and pathological significance of the different α-synuclein splicing variants remains unknown, these isoforms have been associated with intracellular aggregations [26][27][28][29]. Though accelerated fibrillogenesis and enhanced aggregation was expected with the deletion of the functional domains [10,29], the alternative isoforms actually aggregate less than the canonical isoform SNCA140 [12].…”

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confidence: 99%

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18F-AV133 Cerebral VMAT2 Binding Correlated with α-synuclein Spliced Variants in Parkinson’s Disease

Gao¹,

Zhang²,

Chen³

et al. 2016

J Neuroimaging Psychiatry Neurol

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confidence: 69%

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confidence: 99%

18F-AV133 Cerebral VMAT2 Binding Correlated with α-synuclein Spliced Variants in Parkinson’s Disease

Gao¹,

Zhang²,

Chen³

et al. 2016

J Neuroimaging Psychiatry Neurol

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“…Part of our present data underline these results showing the drastic diminution of all SNCB transcripts in the cortex of G-pDLB. Noteworthy, that the same samples are also characterized by the overexpression of aggregation-prone isoforms SNCA112 and SNCA98, accompanied by the reduction of the whole transcript SNCA140, and the potentially protective isoform SNCA126 [10,12,13]. Taken together, there is a decrease in the expression of all SNCB isoforms, SNCA140 and protective SNCA126, but an increase in the expression of both aggregation-prone SNCA isoforms.…”

Section: Discussionmentioning

confidence: 91%

“…Moreover, it has been reported that the accumulation of small presynaptic AS aggregates correlates with dendritic spine loss causing neurodegeneration in DLB [9]. So far, four different splice variants of the AS gene (SNCA) have been described [10], and alterations in their differential expression could represent one of the molecular mechanisms leading to AS oligomerization and aggregation [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

New brain-specific beta-synuclein isoforms show expression ratio changes in Lewy body diseases

et al. 2011

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Lewy body diseases (LBDs) include dementia with Lewy bodies (DLB) and Parkinson disease (PD). Alpha-synuclein (AS) aggregation is a key event in the pathogenesis of LBDs and beta-synuclein (BS) inhibits AS aggregation in vitro and in vivo. Recently, BS has been shown to interact directly with AS regulating its functionality and preventing its oligomerization, and a molecular subgroup of pure DLB lacks BS in cortical regions. In this study, we characterized four new BS transcript variants and analyzed their expression in neuronal and non-neuronal tissue, and their differential expression in frozen samples of three areas from brains of patients with pure Lewy body pathology (LBP), common LBP, Alzheimer pathology, and of controls. Relative mRNA expression was determined by real-time PCR with neuron-specific enolase 2 and synaptophysin as housekeeping genes, and expression changes were evaluated by the ΔΔCt method. Two main findings are in concordance with earlier studies. First, all BS isoforms are drastically diminished in the cortex of patients with pure LBP that had presented clinically as DLB but not PD with dementia. Second, an important shift of the isoform expression ratio was observed in the temporal cortex of all LBD cases, and the minor isoforms, normally absent in the midbrain, were detected in the caudate nucleus of all DLB samples. Our results provide further evidence for the role of minor transcript variants in the development of complex diseases and provide new insights into the pathogenesis of LBDs that may be important for the understanding of molecular mechanisms involved in these complex diseases.

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“…Recent discoveries highlight that alternative splicing of α-syn may also play a crucial role in the mechanisms mediating PD [28]–[31]. So far, deletion of exon 3 [126-Syn] or exon 5 [112-Syn] or both exon 3 and 5 [98-Syn] have been identified [32], [33].…”

Section: Introductionmentioning

confidence: 99%

The Chaperone-Like Activity of α-Synuclein Attenuates Aggregation of Its Alternatively Spliced Isoform, 112-Synuclein In Vitro: Plausible Cross-Talk between Isoforms in Protein Aggregation

et al. 2014

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Abnormal oligomerization and aggregation of α-synuclein (α-syn/WT-syn) has been shown to be a precipitating factor in the pathophysiology of Parkinson's disease (PD). Earlier observations on the induced-alternative splicing of α-syn by Parkinsonism mimetics as well as identification of region specific abnormalities in the transcript levels of 112-synclein (112-syn) in diseased subjects underscores the role of 112-syn in the pathophysiology of PD. In the present study, we sought to identify the aggregation potential of 112-syn in the presence or absence of WT-syn to predict its plausible role in protein aggregation events. Results demonstrate that unlike WT-syn, lack of 28 aa in the C-terminus results in the loss of chaperone-like activity with a concomitant gain in vulnerability to heat-induced aggregation and time-dependent fibrillation. The effects were dose and time-dependent and a significant aggregation of 112-syn was evident at as low as 45°C following 10 min of incubation. The heat-induced aggregates were found to be ill-defined structures and weakly positive towards Thioflavin-T (ThT) staining as compared to clearly distinguishable ThT positive extended fibrils resulting upon 24 h of incubation at 37°C. Further, the chaperone-like activity of WT-syn significantly attenuated heat-induced aggregation of 112-syn in a dose and time-dependent manner. On contrary, WT-syn synergistically enhanced fibrillation of 112-syn. Overall, the present findings highlight a plausible cross-talk between isoforms of α-syn and the relative abundance of these isoforms may dictate the nature and fate of protein aggregates.

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Low alpha-synuclein 126 mRNA levels in dementia with Lewy bodies and Alzheimer disease

Cited by 47 publications

References 24 publications

18F-AV133 Cerebral VMAT2 Binding Correlated with α-synuclein Spliced Variants in Parkinson’s Disease

18F-AV133 Cerebral VMAT2 Binding Correlated with α-synuclein Spliced Variants in Parkinson’s Disease

New brain-specific beta-synuclein isoforms show expression ratio changes in Lewy body diseases

The Chaperone-Like Activity of α-Synuclein Attenuates Aggregation of Its Alternatively Spliced Isoform, 112-Synuclein In Vitro: Plausible Cross-Talk between Isoforms in Protein Aggregation

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