Junn E, Lee KW, Jeong BS, Chan TW, Im JY, Mouradian MM.
Repression of alpha-synuclein expression and toxicity by microRNA-7.
Proc Natl Acad Sci U S A. 2009 Aug 4;106(31):13052-7.
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This paper adds to the growing evidence that microRNAs could be involved in neurodegenerative diseases. Here, Junn and colleagues provide interesting data suggesting that α-synuclein (SNCA) mRNA is regulated at the post-transcriptional level by miR-7, a microRNA enriched in the pituitary gland and expressed at relatively high levels in the brain. Similar to APP in Alzheimer’s, gene dosage effects of SNCA can cause familial Parkinson disease (PD). Thus, these new results raise the interesting possibility that microRNAs could play a role in genetic and sporadic PD.
The 3’UTR of human SNCA is quite long (approximately 1000 nt in length) and relatively well conserved, thus suggesting its biological importance. From various prediction programs found online (TargetScan, Pictar, miRBase, miRanda), a few microRNA candidates consistently stand out (e.g., miR-7 and miR-153). Here, the authors focus their efforts on miR-7. We would like to comment on some of the salient observations reported by the authors.
First, the authors show that overexpression of miR-7 in HEK293T cells causes a downregulation of endogenous SNCA protein and mRNA levels. Inversely, inhibition of endogenous miR-7 in neuronal SH-SH5Y cells using antisense probes results in an increase in SNCA protein and mRNA (note that they did/could not perform gain-of-function studies in these cells). While these observations are promising, the presented data in Figures 1 and 3 lack the appropriate scrambled controls to determine whether the effect on endogenous SNCA expression is genuine. The authors also demonstrate that miR-7 protects against SNCA-induced proteasome inhibition and cytotoxicity (Figure 4). While the authors observe a striking effect of miR-7 on cell survival after SNCA A53T expression, one should remain cautious, as these studies were all performed in overexpression paradigms.
A salient question is whether miR-7 and SNCA are co-expressed in the same cell type in the brain, particularly in the substantia nigra. Here, the authors show that miR-7 is relatively more abundant (about 50 percent) in the mouse substantia nigra than in cortex. This is in line with earlier observations (Kim et al., 2007). They also show that this microRNA is mainly expressed in cultured mouse cortical neurons as compared to astrocytes. Unfortunately, no experimental evidence indicating that SNCA is regulated by miR-7 in primary neurons is provided (only correlative evidence is given). In line with the previous comment, it would have been very informative to check SNCA expression levels (preferably protein expression) in the ventral midbrain tissue of the same MPTP-treated mice that were used to analyze miR-7 expression.
If we consider that miR-7 regulates SNCA in vivo, it would be very interesting to investigate miR-7 expression and correlation with SNCA levels in PD patients in general, and SNCA A53T mutated cases in particular. Of note, Kim et al. showed that levels of miR-7 do not change in PD patients. At most, this latter study suggests there is increased expression of miR-7, which would not correlate with increased SNCA expression. An interesting possibility is that only a subgroup of patients display changes in miR-7.
With respect to this work, a previous study on miR-7 in Drosophila (dm-miR-7) demonstrated that dm-miR-7 is important to generate biological robustness in genetic networks (Li et al., 2009). The authors of this paper suggest that dm-miR-7 buffers gene expression against environmental fluctuation. The fact that this function of dm-miR-7 is exposed under fluctuating conditions underscores its primary role as a stabilizer for the development of the fly’s sensory organs. It is interesting to speculate whether this function of miR-7 is conserved in mammals and how it might correlate with the development of PD. For instance, could PD caused by environmental factors—such as living in rural areas with exposure to herbicides—involve changes in miR-7 levels? Or in the case of genetic forms of PD, would reduced miR-7 activity lead to increased penetrance of the disease?
In spite of some gaps, the present study clearly contributes to our understanding of the emerging critical role of miRNAs in neurodegenerative disease and PD in particular. This certainly opens the door to for further exciting studies into the role of microRNAs in the regulation of expression of SNCA and other PD-associated genes in vivo and in disease.
Kim J, Inoue K, Ishii J, Vanti WB, Voronov SV, Murchison E, Hannon G, Abeliovich A.
A MicroRNA feedback circuit in midbrain dopamine neurons.
Science. 2007 Aug 31;317(5842):1220-4.
Li X, Cassidy JJ, Reinke CA, Fischboeck S, Carthew RW.
A microRNA imparts robustness against environmental fluctuation during development.
Cell. 2009 Apr 17;137(2):273-82.