Nature Cell Biology 3, pp 503 - 506

In the May issue of Nature Cell Biology (3, 503-506), Pierre Coulombe and colleagues, of the Johns Hopkins University School of Medicine in Baltimore, USA, describe the molecular effect of one mutation commonly found in a keratin gene of patients affected by the skin fragility disorder epidermolysis bullosa simplex (EBS).

Keratins are proteins that form rod-like structures and assemble as a criss-crossed web within skin cells to give them structure and support from outside pressure. (Just imagine what's happening to these cells when someone squeezes your arm or pinches your skin!) In EBS, mutations can occur in two of the many keratin genes present in skin cells. Coulombe and coworkers describe the mechanical properties of one of these defective keratin proteins. The mutation in keratin 14 changes a single amino acid, with dramatic effect. Whereas the normal protein makes filaments which then form bundles, like a sheaf of wheat, the mutated keratin protein cannot form the bundles, and consequently produces keratin networks that are more prone to breaking under stress. In addition, this mutant keratin makes filaments of greatly varying lengths, another factor expected to lower a cell's resilience to external stress.

Whilst these results suggest how this particular mutation might contribute to the manifestation of EBS, further studies are required to determine how other keratin-based disorders, which do not affect filament structure so obviously, cause similar skin fragility disorders.

Nature Cell Biology 3, pp 507 - 511

Fréderic Checler from the Institut de Pharmacologie Moleculaire et Cellulaire in Nice, France, and Jean-Louis Kraus from Trophos, Inc., Marseille, France, now describe in the May issue of Nature Cell Biology new synthetic drugs that specifically target what may be the causal event of Alzheimer's disease (AD), without any obvious side effects.

Patients with Alzheimer's disease (AD) accumulate aggregates of the Amyloid-β protein (A-β) in their brain. Whether this is a cause or a consequence of the disease is still a matter of debate, but there is some evidence supporting the former hypothesis: when incubated with A-β in vitro, neurons die and immunization with A-β seems to vaccinate mice from AD.

A-β is the product of cleavage of its precursor, amyloid precursor protein, by an enzyme called γ-secretase. Blocking this enzyme might, therefore, prevent the accumulation of A-β and hence the progression of AD.

But, as γ-secretase has other substrates (such as the Notch protein and possibly the Ire1 protein) which are involved in essential processes such as defence, cell differentiation and response to stress, drugs developed to block it might have undesirable secondary effects.

Checler and Kraus have now synthesized new drugs that specifically affect A-β generation by γ-secretase, without affecting γ-secretase cleavage of other substrates.