Editor’s note: Science Scan is a roundup of recently published biotechnology-relevant research.
Can you name the commonest inherited neurological disease of them all? No, it’s not multiple sclerosis or amyotrophic lateral sclerosis. It’s Charcot-Marie-Tooth disease (CMT), otherwise known as peroneal muscular atrophy. Its prevalence in the United States is at least one CMT person in 2,500, for a total estimated patient population of some 130,000. But since CMT is far from life-threatening, its true body count may reach twice that number.
Circa 1896, French neurologist Jean-Martin Charcot and his student, Pierre Marie, first described peroneal muscular atrophy. Coincidentally, British neurologist Howard Henry Tooth did likewise giving rise to the eponymous Charcot-Marie-Tooth disease.
“It’s fairly prevalent in Tunisia, Morocco and Ethiopia,” observed human geneticist/neurologist Jeffrey Vance, at Duke University in Durham, N.C. “CMT is found in Spain as well,” he added, “presumably among people of Arabian descent.” Vance is senior author of a research paper in the January 2002 issue of Nature Genetics. Its title: “Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q2l.”
Back to back with Vance’s paper is a companion piece titled: “The gene encoding ganglioside-induced differentiation-associated protein-1 is mutated in axonal Charcot-Marie-Tooth type 4A disease.” Its authors are neurologists at the University Hospital in Valencia, Spain.
These twin articles reflect CMT’s dual neurological nature. In fact, it’s two diseases an axonal version that attacks sensory axons, and another that demyelinates those axons.
“We were studying the autosomal recessive form of the disease,” Vance recounted, “which affects kids usually within the first or second year of life. The families we looked at were from Tunisia. We don’t know if this particular demyelinating form occurs in the U.S., but we suspect it does. We had been studying these families for quite a few years and were now able to identify the gene that causes this particular form of the neuropathy.
“The Spanish paper reported on the axonal form of CMT,” Vance observed, “and ours studied the demyelinating form. In those two neuropathies, the nerve cells will be distinctly different as to their etiologies. The phenomenon was expected because the protein this gene encodes is involved in cell differentiation, so it wasn’t expected to have anything to do with the neuropathy. It suggested some sort of new mechanism for getting this dual form of CMT.
“The other thing that interested us,” Vance continued, “is that the Spanish paper’s authors studied the axonal form and we the demyelinating version. In those two disparate neuropathies, the nerve cells will be distinctly different in their etiologies.
“We don’t have any clue as to what this gene does, or why it can cause this dual neuropathy,” Vance concluded. “That will probably open up a whole bunch of interesting research areas, beginning, in our case, with construction of an animal model.”
Pfizer, Sangamo Molecular Scientists Team Up To Demonstrate Anti-Obesity Drug Factors
Repressed expression of the PPARg gene a prime player in development of fat cells (adipocytes) is reported as the cover story in the Jan. 8, 2002, issue of the journal Genes & Development (published twice monthly by the Cold Spring Harbor Press). The paper bears the title: “PPARg knockdown by engineered transcription factors: exogenous PPARg2 but not g1 reactivates adipogenesis.” Its authors are molecular scientists at Pfizer Global and Research Development in Ann Arbor, Mich., and at Sangamo BioSciences Inc., of Richmond, Calif.
This contribution to anti-obesity R&D describes identification of the specific gene variant critical to adipocyte development. “The function of this gene isoform, PPARgamma 2,” Sangamo scientists reported in a media teleconference on Dec. 31, 2001, “expresses a highly specific molecular target for potential new drug development in obesity as well as diabetes, cardiovascular disease and cancer.” The firm’s technology centers on a proprietary zinc-finger protein transcription factor that controls gene expression.
“The nuclear receptor is required for adipogenesis,” their paper explains. “It’s expressed as two splice variants the widely distributed g1 and adipocyte-specific g2.” In an in vivo experiment, the article reports “selective repression of the endogamous g2-specific P2 promoter, which reduced g2 expression by more than 50 percent, without affecting g1. This led to 50 percent reduction in adipogenesis.”
The authors conclude that their finding, “provides the first clear demonstration of a selective role for PPARg2 during adipogenesis.”
Elsewhere On Obesity Front, A Coenzyme Named Q’ Mediates Youthful Fitness, Old Age
Eating less leads to living longer for many animals, including humans, But what you eat may also figure in this equation at least if you’re a worm. When biochemists at UCLA, Los Angeles, fed Caenorhabditis elegans nematodes a diet of the coenzyme Q, the worms’ life span went up 60 percent.
The team’s article in Science, dated Jan. 4, 2002, suggests that less Q means fewer cell-damaging oxygen radicals released as a respiration by-product. That paper is titled: “Extension of life-span in Caenorhabditis elegans by a diet lacking coenzyme Q.” Coenzyme Q carries electrons and protons across the inner mitochondrial membrane, as part of that power-house organelle’s cellular respiration process.
Worms depend on their clock gene to scarf up Q from their diet of wild-type E. coli bacteria that synthesize the coenzyme.
A “Perspective” editorial observes: “The ability to assimilate dietary Q and to synthesize endogenous Q supports growth and development, and clearly increases components of fitness expressed at young ages. This physiological capacity, however, reduces adult survival. Senescence can evolve under these conditions because the strength of natural selection is greatest upon traits expressed early in the life cycle.
“Ultimately,” the commentary concludes, “to establish the generality of Q’s aging effects, we must also test its impact in organisms such as the fruit fly Drosophila and rodents, where the influence of fermentation pathways is likely to be different.”