Rademakers R, Eriksen JL, Baker M, Robinson T, Ahmed Z, Lincoln SJ, Finch N, Rutherford NJ, Crook RJ, Josephs KA, Boeve BF, Knopman DS, Petersen RC, Parisi JE, Caselli RJ, Wszolek ZK, Uitti RJ, Feldman H, Hutton ML, Mackenzie IR, Graff-Radford NR, Dickson DW. Common variation in the miR-659 binding-site of GRN is a major risk factor for TDP43-positive frontotemporal dementia. Hum Mol Genet. 2008 Dec 1;17(23):3631-42. PubMed.
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Laval University
The manuscript by Rademakers and colleagues provides evidence that increased binding of miR-659 to the 3’UTR of the GRN gene could underlie an important risk for TDP-43-positive frontotemporal dementia (FTLD-U). These data bring strong clinical support for the role of microRNAs in neurodegenerative disorders in humans. These results are consistent with a loss of function of the GRN gene in the disease, further linking gene dosage effects in neurodegenerative disorders (as seen, e.g., with APP in Alzheimer disease and SNCA in Parkinson disease).
I think Amber Dance did a fantastic job reviewing the highlights of this paper. I would like to discuss additional issues with regard to certain technical and mechanistic aspects of these findings, which could be taken into account when interpreting the data.
First, miR-659, located on chromosome 22 in humans, seems to be relatively very weakly expressed in adult brain (with cycle threshold [Ct] values of approximately 32 as measured by qRT-PCR). Therefore, whether endogenous miR-659 levels are sufficient to regulate GRN levels in vivo remains speculative. Mechanistically, one must envisage that regulation of GRN mRNA by miR-659 occurs in a cell-autonomous fashion. One possibility, not shown here, is that miR-659 is expressed in specific cell types, such as the granular cell layer of the cerebellum where GRN protein is decreased (it should be noted that the qRT-PCR for miR-659 was performed on whole tissues). In my opinion, this would strongly strengthen the biological significance of the proposed mode of regulation.
Here, the authors use basic, but widely accepted in vitro systems to validate their hypothesis. First, artificial overexpression of miR-659 (at a concentration of 12 nM) in human M17 neuroblastoma cells leads to decreased expression of endogenous GRN protein levels (note that inverse experiments using antisense oligonucleotides to block endogenous miR-659 was not performed, possibly due to the extremely low levels of this microRNA in these cells). Whether GRN mRNA levels are affected in these conditions is not shown. Then, additional studies were conducted in mouse Neuro2A cells using luciferase-based constructs containing the GRN 3’UTR. In these latter experiments, functional effects on GRN expression are seen with the mutant TT construct at concentrations starting at 5 pM of exogenous miR-659. Again from a mechanistic point of view, it would be interesting to see whether the “increased” binding (i.e., increased sequence complementarity) of miR-659 to the mutant TT allele causes an siRNA effect (thus degradation of mRNA). It should be noted, however, that, in affected patients, GRN mRNA (from total tissue sections) is not affected.
Interestingly, the predicted target site (more particularly the “seed” sequence) for miR-659 in the GRN 3’UTR is only conserved in humans, and is not found in other mammals including mouse and dog (e.g., see www.targetscan.org). Similarly, miR-659 is, at least for now, only found in humans. Interestingly, the GRN 3’UTR is quite short (approximately 300 bp in length). In comparison, the BACE1 and APP 3’UTRs, which equally have functional microRNA target sites, are approximately 4,000 bp and 2,000 bp in length, respectively.
Overall, these findings provide novel and important clues into the development of FTLD-U. In addition, this study contributes to the potential role of microRNA pathways in the development of neurodegenerative disorders in human. I agree that relatively few patients were analyzed here to make definitive conclusions with regard to the biological relevance of these findings.
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