Rhinn H, Qiang L, Yamashita T, Rhee D, Zolin A, Vanti W, Abeliovich A.
Alternative α-synuclein transcript usage as a convergent mechanism in Parkinson's disease pathology.
Nat Commun. 2012;3:1084.
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This article of Rhinn and colleagues is interesting. They are suggesting that alternative 3’UTR lengths in the α-synuclein gene (SNCA) determine protein expression, accumulation, and localization, which can all alter the risk of Parkinson’s disease. Their idea that specific 3’UTR length (and genetic variation therein) can affect protein expression and localization is intriguing. The underlying disease mechanism at the SNCA locus is a major area of research and may well determine future therapeutic intervention strategies. This work also highlights the need for careful consideration of potential knockdown therapies, as it may be a specific transcript of SNCA that is toxic, limiting a general knockdown strategy.
The authors highlight the two predominant transcripts, but there are a number of other species that may be of interest, and determining the reason for altered 3’UTR expression may be important.
SNCA is located in a large linkage disequilibrium block with risk variants along the length of the gene; hence, in the past, promoter variants such as the REP1 repeat have also been shown to affect SNCA expression. Therefore, given the complexity of mechanisms regulating synuclein gene and protein expression, the modest effect of this 3’UTR-directed risk may well be confounded by others. For example, studies of patient tissue have shown reduced SNCA gene expression, although that is not examining specific transcripts. Furthermore, the authors note that they observe the same SNCA 3’UTR transcript expression pattern in cerebral cortex tissue, which perhaps questions the direct role of this mechanism in the cell death that characterizes Parkinson’s disease.
There are a number of SNCA mRNA transcripts reported with alternative splicing of exon 3 and/or exon 5 (see Beyer et al., 2008). It would be interesting to know if these coding transcripts correlate with the 3’UTR transcripts from the expression point of view. In addition, the authors mention miR34b, but there are several miRNA binding sites, and it is not clear how the others are affected within the setting of alternate 3’UTR lengths.
I think, as with many similar studies, this work raises more questions regarding the complexity of the genetic risk observed in sporadic patients for the SNCA locus. Teasing out the underlying functional genetic variants and then characterizing them will be crucial steps in developing SNCA-based drugs.
Beyer K, Domingo-Sàbat M, Humbert J, Carrato C, Ferrer I, Ariza A.
Differential expression of alpha-synuclein, parkin, and synphilin-1 isoforms in Lewy body disease.
Neurogenetics. 2008 Jul;9(3):163-72.
The manuscript and its data are outstanding. I believe it will change our view of the pathogenesis of Parkinson's disease. The authors make use of intelligent bioinformatic approaches (differential coexpression analysis) to identify a specific transcript isoform of α-synuclein with a long 3′ untranslated region (UTR), termed aSynL, that is highly altered in coexpression correlation in the context of PD tissue. Without describing their whole approach, their new data allow the authors to integrate current knowledge of genetic risk variants, explain the vulnerability of dopaminergic midbrain neurons, integrate mechanisms of known toxins, describe effects of L-DOPA, and explain mislocalization of α-synuclein to mitochondria, which has been a focus in the field (including ours) during the last years.
It will take some time to really appreciate all the details that are given here and to give full credit to the authors. Of course, the data will need replication. However, based on the detailed descriptions in the manuscript, I have not much doubt that the story will hold true.
These authors used an emerging bioinformatics technique (differential coexpression) to identify a mature α-synuclein mRNA transcript that retains an elongated 3’UTR (aSynL) as a potential common pathogenic mechanism for Parkinson's disease (PD).
By applying differential coexpression analysis, aSynL was identified as a potential convergent mechanism of several biological pathways reconfigured in association with PD genetic and environmental risk factors. Their findings highlight the importance of abnormal RNA processing in PD research, particularly since the authors show that aSynL transcripts show pathological significance.
These set-wise, coexpression changes as causal should, however, be approached with caution. For example, coexpression changes found in postmortem PD neurons may not represent causal pathological processes, but rather, may represent a reconfiguration of the existing neuron towards a survival state.
I must say that this is a beautiful and incredibly extensive study that ties together many of the loose ends of the α-synuclein story. It is a scholarly example of how one and the same gene can either contribute 100 percent to disease causality or increase relative risk for that same disease. It demonstrates well the use of public databases and bioinformatics analysis of expression data. Data are also extensively validated using brain material of patients and control individuals, primary cells, transgenic animals, etc. Ultimately, the study provides evidence for the higher sensitivity of midbrain dopaminergic neurons for underlying disease processes.
I believe that this is a milestone paper in our quest for more understanding of the complex brain pathology observed in neurodegenerative brain diseases.