Bringing Insights and iPSCs to Bear on Parkinson’s
What's Hot in Biology, July/August 2010
By Dr. Jeremy Cherfas
Two new papers offer glimpses of additional insights into the fundamentals of Parkinson's disease. At #7, Rudolf Jaenisch's group at the Whitehead Institute for Biomedical Research in Cambridge, Massachusetts, outlines the procedure for reprogramming skin cells from Parkinson's patients into pluripotent stem cells with none of the drawbacks previously associated with such reprogramming.
And, in a paper just below the Top Ten, Richard Youle and his colleagues at the National Institute of Neurological Disorders and Stroke in Bethesda, Maryland, pinpoint the function of one of the genes associated with Parkinson's (D. Narendra, et al., J. Cell Biology, 183[5]: 795-803, 1 December 2008; 23 citations this period, 82 overall, currently ranked at #17).
Parkinson's disease is one of the most common progressive neurodegenerative diseases. It is associated with a loss of dopaminergic neurons in the brain, and by far the majority of cases are sporadic, having no known heritable component. A small minority of cases, however, often of early-onset Parkinson's, are familial, and these have been linked to several different genes.
The most common mutation associated with Parkinson's is in the Park2 gene, which codes for a protein called Parkin. Parkin is a ubiquitin ligase; it joins molecules of ubiquitin to targets on molecules and organelles, often marking the targeted organelles for destruction. It was known that Parkin had something to do with the regulation of defective mitochondria, the organelles that supply the cell with energy, and that neurons in cases of Parkinson's are often poorly supplied with functional mitochondria, but the links were unclear.
Youle and his colleagues treated cells with a chemical known to damage mitochondria. Within an hour, Parkin was found attached to the damaged mitochondria, which were then engulfed by clean-up bodies and destroyed. Cells that lack certain genes important for mitochondrial function accumulate a series of defective mitochondria, and Parkin attaches to these too and signals their destruction.
"One of the difficulties facing researchers investigating brain diseases such as Parkinson's and Alzheimer's is that it is not easy to obtain diseased cells to study."
A series of careful experiments confirmed that Parkin is attracted to defective mitochondria and promotes their degradation. Further details of the causal chain await elucidation, but Youle's group speculates that long-lived cells, such as neurons, require finer control over defective mitochondria than rapidly dividing cells, in which an accumulation of malfunctioning mitochondria could trigger cell death and thus get rid of the damage. Mutations in Park2 in such long-lived cells could lead to an accumulation of defective mitochondria and thus to loss of function in the neurons. If that is so, then restoring Parkin, or another ubiquitin ligase, might restore the health of the neurons.
One way to restore neuron function, which has been tried with some success, is to transplant embryonic cells into the brains of patients. This kind of therapy has come closer with the discovery that adult cells can be reprogrammed into pluripotent cells capable of differentiating into any type of cell. Induced pluripotent stem cells (iPSCs), however, require the use of viral gene sequences that bring with them a risk of cancer. (See, for example, the Biology Top Ten discussions for January/February 2010 and July/August of 2008).
Jaenisch and his colleagues surrounded the inducing sequences with another target sequence that is recognized by the Cre enzyme. This enzyme causes recombination between two pieces of DNA, removing the segment between the two Cre target sites. By adding the gene for the Cre enzyme to transformed skin cells from Parkinson's patients, the researchers snipped out the signals that had reprogrammed the skin cells, resulting in iPSCs that retained their ability to differentiate into, for example, dopaminergic neurons, but that had none of the inserted reprogramming DNA left, and thus suffered none of the risks of turning cancerous.
Previous attempts to remove the reprogramming signals have been very inefficient and have resulted in the loss of pluripotency. This result marks a turning point in the protocols for reprogramming cells.
The researchers went further, and studied in detail the gene-expression profile of their transformed cells. The reprogramming factors are known to bind to and affect the functioning of at least 3,000 genes in the average cell. No wonder, then, that iPSCs have a different pattern of gene activity. Excising the factors with the Cre enzyme restores gene activity to a pattern much more like that of genuine human embryonic stem cells than that of "conventional" iPSCs.
One of the difficulties facing researchers investigating brain diseases such as Parkinson's and Alzheimer's is that it is not easy to obtain diseased cells to study. The ability to turn skin cells from Parkinson's patients into dopaminergic neurons, with whatever faults they may have that cause the disease, is thus a considerable breakthrough. And the ability to study diseased cells in large numbers may make it easier to search for therapies, possibly based on restoring the function of Parkin produced by defective Park2 genes.
Dr. Jeremy Cherfas is Science Writer at Bioversity International in Rome, Italy.
What's Hot in Biology | |||
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Rank | Paper |
Cites This Period Jan-Feb 10 |
Rank Last Period Nov-Dec 09 |
1 | D. Baek, et al., "The impact of microRNAs on protein output," Nature, 455(7209): 64-71, 4 September 2008. [Whitehead Inst., Cambridge, MA; Howard Hughes Med. Inst., MIT, Cambridge; Harvard Med. Sch., Boston, MA] *343XS | 43 | 3 |
2 | S.A. Mani, et al., "The epithelial-mesenchymal transition generates cells with properties of stem cells," Cell, 133(4): 704-15, 16 May 2008. [8 U.S. and Swiss institutions] *301NQ | 39 | 6 |
3 | M. Selbach, et al., "Widespread changes in protein synthesis induced by microRNAs," Nature, 455(7209): 58-63, 4 September 2008. [Max Delbruck Ctr. Molec. Med., Berlin, Germany; U. Glasgow, U.K.] *343XS | 36 | 5 |
4 | E. Zeggini, et al., "Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes," Nature Genetics, 40(5): 638-45, May 2008. [5 U.S. and U.K. institutions] *293WS | 35 | 4 |
5 | D.R. Bentley, et al., "Accurate whole genome sequencing using reversible terminator chemistry," Nature, 456(7218): 53-9, 6 November 2008. [7 European and U.S. institutions] *369DH | 34 | 8 |
6 | I.H. Park, et al., "Disease-specific induced pluripotent stem cells," Cell, 134(5): 877-86, 5 September 2008. [9 U.S. and German institutions] | 33 | † |
7 | F. Soldner, et al., "Parkinson’s disease patient-derived induced pluripotent stem cells free of viral reprogramming factors," Cell, 136(5): 964-77, 6 March 2009. [Whitehead Inst., Cambridge, MA; MIT, Cambridge; McLean Hosp./Harvard Med. Sch., Belmont, MA] *415JU | 28 | † |
8 | J.C. Barrett, et al., "Genome-wide association defines more than 30 distinct susceptibility loci for Crohn’s disease," Nature Genetics, 40(8): 955-62, August 2008. [31 institutions worldwide] *331QF | 26 | 2 |
9 | D.A. Wheeler, et al., "The complete genome of an individual by massively parallel DNA sequencing," Nature, 456(7218): 872-7, 17 April 2008. [6 U.S. institutions] *288ZY | 26 | † |
10 | J. Wang, et al., "The diploid sequence of an Asian individual," Nature, 456(7218): 60-5, 6 November 2008. [11 institutions worldwide] *369DH | 26 | † |
SOURCE: Thomson Reuters Hot Papers Database. Read the Legend. |
KEYWORDS: STRAINED, SI, SIGE, GE, METAL-OXIDE SEMICONDUCTOR FIELD-EFFECT TRANSISTORS, MOSFETS, HIGH ELECTRON MOBILITY, MOLECULAR BEAM EPITAXY, THREADING DISLOCATION DENSITIES, SILICON INVERSION LAYERS, MODULATION DOPED SI/SIGE, ON INSULATOR LAYERS, HIGH HOLE MOBILITY, P-TYPE, RELAXED SI1-XGEX, N-MOSFETS.
Citing URL: http://sciencewatch.com/ana/hot/bio/10julaug-bio/