Schaefer A, O'Carroll D, Tan CL, Hillman D, Sugimori M, Llinas R, Greengard P.
Cerebellar neurodegeneration in the absence of microRNAs.
J Exp Med. 2007 Jul 9;204(7):1553-8.
PubMed.
Anne Schaefer et al. have produced an important study about miRNAs in the mouse cerebellum. Their data suggest that miRNA function is critical for mammalian neuronal survival. The authors conclude that since dicer downregulation causes neuronal cell death, then some human neurodegenerative diseases may be caused by loss of small regulatory RNAs. (The authors wrote, “this pattern of Purkinje cell degeneration in the absence of miRNAs bears obvious similarity to processes associated with the slow progressing neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.” The “obviousness” is open to debate and surely one would draw closer analogies to the spinocerebellar ataxias because neurodegenerative diseases seem to be very cell type-specific). This is the first such study in mammals, although intriguing prior studies have previously been performed by the Bonini lab at U. Penn on flies using genes relevant to spinocerebellar ataxia.
From a technical standpoint, the paper is solid, as one would expect from the outstanding Greengard laboratory. In their mice, Purkinje cell-specific Pcp2 promoter drives a Cre recombinase that causes the dicer gene (modified with loxP sites) to be knocked down. The dicer gene gets knocked down after the second week of life because that’s when the Pcp2 gene is activated. In situ hybridization shows dramatically reduced expression of some, but not all, Purkinje cell miRNAs after dicer knockdown. Most of the rest of the study is essentially
neuropathological: loss of expression of both dicer and most miRNAs is followed by Purkinje cell death, dendritic withering, and, as would be expected, an ataxia phenotype develops in the mice.
Key points:
1. Some neurons need dicer (read: some miRNAs) to survive—an important point, and not one to be taken for granted!
Key additional questions:
1. Was it for want of miRNAs or some other dicer-related function that caused the cells to die?
2. If lack of miRNAs caused the cell death, was it one or a group of miRNAs that were necessary for cell viability (in coming years, we’ll no doubt see some specific miRNA knockout mice with specific phenotypes)?
3. Related but separate question—which critical biological functions in cells are regulated by those vital miRNAs?
4. Why are some miRNAs still evidently present in these cells after dicer is knocked out?
5. How do these results correlate to other types of neurodegeneration?
The field of miRNA research is in its infancy—small regulatory RNAs were the journal Science’s “Discovery of the Year” in 2002, and related research won the Nobel Prize in Medicine and Physiology in 2006. MiRNAs are short (~22 nts) RNA molecules that play remarkably powerful biological roles in plants and all known animals. MiRNAs appear to act by regulating “target” mRNAs, to which their sequences are partly complementary. Constituting ~5 percent of the human transcriptome, miRNAs in turn are predicted to regulate >30 percent of known mRNAs. MiRNAs have been shown to be expressed at high levels in brain, where hundreds of different miRNAs (most still not annotated!) are expressed in human and chimpanzee brains according to work from many labs including the Plasterk Lab in the Netherlands. A discrete role for miRNAs in human brain disease has yet to be found. However, with studies like these from the Greengard lab emerging, miRNAs may indeed play a role in human neurodegeneration with important clinical implications.
Comments
University of Kentucky
Anne Schaefer et al. have produced an important study about miRNAs in the mouse cerebellum. Their data suggest that miRNA function is critical for mammalian neuronal survival. The authors conclude that since dicer downregulation causes neuronal cell death, then some human neurodegenerative diseases may be caused by loss of small regulatory RNAs. (The authors wrote, “this pattern of Purkinje cell degeneration in the absence of miRNAs bears obvious similarity to processes associated with the slow progressing neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease.” The “obviousness” is open to debate and surely one would draw closer analogies to the spinocerebellar ataxias because neurodegenerative diseases seem to be very cell type-specific). This is the first such study in mammals, although intriguing prior studies have previously been performed by the Bonini lab at U. Penn on flies using genes relevant to spinocerebellar ataxia.
From a technical standpoint, the paper is solid, as one would expect from the outstanding Greengard laboratory. In their mice, Purkinje cell-specific Pcp2 promoter drives a Cre recombinase that causes the dicer gene (modified with loxP sites) to be knocked down. The dicer gene gets knocked down after the second week of life because that’s when the Pcp2 gene is activated. In situ hybridization shows dramatically reduced expression of some, but not all, Purkinje cell miRNAs after dicer knockdown. Most of the rest of the study is essentially
neuropathological: loss of expression of both dicer and most miRNAs is followed by Purkinje cell death, dendritic withering, and, as would be expected, an ataxia phenotype develops in the mice.
Key points:
1. Some neurons need dicer (read: some miRNAs) to survive—an important point, and not one to be taken for granted!
Key additional questions:
1. Was it for want of miRNAs or some other dicer-related function that caused the cells to die?
2. If lack of miRNAs caused the cell death, was it one or a group of miRNAs that were necessary for cell viability (in coming years, we’ll no doubt see some specific miRNA knockout mice with specific phenotypes)?
3. Related but separate question—which critical biological functions in cells are regulated by those vital miRNAs?
4. Why are some miRNAs still evidently present in these cells after dicer is knocked out?
5. How do these results correlate to other types of neurodegeneration?
The field of miRNA research is in its infancy—small regulatory RNAs were the journal Science’s “Discovery of the Year” in 2002, and related research won the Nobel Prize in Medicine and Physiology in 2006. MiRNAs are short (~22 nts) RNA molecules that play remarkably powerful biological roles in plants and all known animals. MiRNAs appear to act by regulating “target” mRNAs, to which their sequences are partly complementary. Constituting ~5 percent of the human transcriptome, miRNAs in turn are predicted to regulate >30 percent of known mRNAs. MiRNAs have been shown to be expressed at high levels in brain, where hundreds of different miRNAs (most still not annotated!) are expressed in human and chimpanzee brains according to work from many labs including the Plasterk Lab in the Netherlands. A discrete role for miRNAs in human brain disease has yet to be found. However, with studies like these from the Greengard lab emerging, miRNAs may indeed play a role in human neurodegeneration with important clinical implications.
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