Find below a link to an article published in Clinical Chemistry by Eleftherios P. Diamandis entitled, “How to Win Wimbledon Championships: Creating Beklof and Vamos”. It’s a funny take on the probability of genetically engineered children in the near future.
http://www.clinchem.org/cgi/content/full/55/6/1253
Monday, June 22, 2009
Rhes and Huntingtin - The odd couple!!
Rhes, a striatal specific protein, mediates mutant-huntingtin cytotoxicity.
Subramaniam S, Sixt KM, Barrow R, Snyder SH.
Science. 2009 Jun 5;324(5932):1327-30.
Huntington’s disease (HD) is an inherited neurodegenerative disorder, characterized by the gradual, irreversible impairment of psychological, motor, and cognitive functions. Symptoms typically appear in middle age, but onset can occur at almost any age. The course of the disease can last 15 to 20 years. The genetic mutation underlying HD has been traced to a gene encoding a protein called Huntingtin (Mr 350,000). The normal function of Huntingtin is not yet known. In individuals who will not develop HD, a region of the gene that encodes the amino terminus of the protein has a sequence of CAG codons (for glutamine) that is repeated 6 to 39 times in succession. In individuals with adult-onset HD, this codon is typically repeated 40 to 55 times. In individuals with childhood-onset HD, this codon is repeated more than 70 times. The length of this simple trinucleotide repeat indicates whether an individual will develop HD, and at approximately what age the first symptoms will occur.
The abnormal Huntingtin protein is produced in almost all cells of the body, but the pathology is limited to the corpus striatum in the brain. In fact, the corpus striatum is almost paper-thin in patients with advanced HD. The possible reason for localization of pathology in what is essentially a global genetic defect is not known. However, the authors of this paper have come up with an explanation to this perplexing phenomenon.
Rhes is a monomeric G protein that is almost exclusively expressed in the corpus striatum. The normal function of Rhes has not been elucidated but it is known to modify proteins by a process called sumolyation. Sumoylation is a post-translational modification. It involves the addition of a small protein called SUMO. SUMO proteins are similar to ubiquitin, and sumoylation is directed by an enzymatic cascade analogous to that involved in ubiquitination. In contrast to ubiquitin, SUMO is not used to tag proteins for degradation. SUMO modification of proteins has many functions like protein stability, nuclear-cytosolic transport, and transcriptional regulation.
In this paper, the authors have shown that Rhes causes the sumoylation of the mutated Huntingtin protein. In the absence of sumoylation, abnormal Huntingtin tends to aggregate within the cell. Sumoylation seems to inhibit this aggregation. It has long been thought that cellular toxicity was caused by the protein aggregates. However, this paper suggests that the soluble form of abnormal Huntingtin is harmful to the cell. Rhes by sumoylating Huntingtin, seemed to inhibit aggregation, thus increasing the concentration of soluble Huntingtin in the cell. Since, Rhes, as pointed out earlier, is exclusively expressed in the corpus striatum, the pathology in HD is therefore localized to the corpus striatum, though all cells in the body have the abnormal gene.
The obvious next step in research in this field would be to find out the normal function of Rhes. This could be done in vivo by using transgenic Rhes knock-out mice and in vitro by siRNA based techiniques. If Rhes is not shown to have critical functions in the cell, a drug that decreases Rhes expression could be the basis of treatment of HD in the future.
Subramaniam S, Sixt KM, Barrow R, Snyder SH.
Science. 2009 Jun 5;324(5932):1327-30.
Huntington’s disease (HD) is an inherited neurodegenerative disorder, characterized by the gradual, irreversible impairment of psychological, motor, and cognitive functions. Symptoms typically appear in middle age, but onset can occur at almost any age. The course of the disease can last 15 to 20 years. The genetic mutation underlying HD has been traced to a gene encoding a protein called Huntingtin (Mr 350,000). The normal function of Huntingtin is not yet known. In individuals who will not develop HD, a region of the gene that encodes the amino terminus of the protein has a sequence of CAG codons (for glutamine) that is repeated 6 to 39 times in succession. In individuals with adult-onset HD, this codon is typically repeated 40 to 55 times. In individuals with childhood-onset HD, this codon is repeated more than 70 times. The length of this simple trinucleotide repeat indicates whether an individual will develop HD, and at approximately what age the first symptoms will occur.
The abnormal Huntingtin protein is produced in almost all cells of the body, but the pathology is limited to the corpus striatum in the brain. In fact, the corpus striatum is almost paper-thin in patients with advanced HD. The possible reason for localization of pathology in what is essentially a global genetic defect is not known. However, the authors of this paper have come up with an explanation to this perplexing phenomenon.
Rhes is a monomeric G protein that is almost exclusively expressed in the corpus striatum. The normal function of Rhes has not been elucidated but it is known to modify proteins by a process called sumolyation. Sumoylation is a post-translational modification. It involves the addition of a small protein called SUMO. SUMO proteins are similar to ubiquitin, and sumoylation is directed by an enzymatic cascade analogous to that involved in ubiquitination. In contrast to ubiquitin, SUMO is not used to tag proteins for degradation. SUMO modification of proteins has many functions like protein stability, nuclear-cytosolic transport, and transcriptional regulation.
In this paper, the authors have shown that Rhes causes the sumoylation of the mutated Huntingtin protein. In the absence of sumoylation, abnormal Huntingtin tends to aggregate within the cell. Sumoylation seems to inhibit this aggregation. It has long been thought that cellular toxicity was caused by the protein aggregates. However, this paper suggests that the soluble form of abnormal Huntingtin is harmful to the cell. Rhes by sumoylating Huntingtin, seemed to inhibit aggregation, thus increasing the concentration of soluble Huntingtin in the cell. Since, Rhes, as pointed out earlier, is exclusively expressed in the corpus striatum, the pathology in HD is therefore localized to the corpus striatum, though all cells in the body have the abnormal gene.
The obvious next step in research in this field would be to find out the normal function of Rhes. This could be done in vivo by using transgenic Rhes knock-out mice and in vitro by siRNA based techiniques. If Rhes is not shown to have critical functions in the cell, a drug that decreases Rhes expression could be the basis of treatment of HD in the future.
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