Broken down protein degradation could lead to neurodegeneration

rpr.JPGThe removal and destruction of abnormal, damaged or unwanted protein molecules is a normal part of cellular housekeeping, with protein turnover taking place continuously.

One method for the removal and degradation of such proteins is the ubiquitin-proteasome pathway. Proteins are targeted for destruction by being ‘tagged’ with ubiquitin molecules. These ubiquitinated proteins are recognized by the proteasome, a multi-subunit proteolytic enzyme complex.

The other process by which proteins are degraded is (macro)autophagy, during which contents of the cytoplasm are enveloped in vesicles called autophagosomes and delivered to the lysosome, an organelle which breaks them down.

The preferred substrates of the proteasome are single, unfolded protein molecules. The abnormally folded aggregates of proteins which characterize Alzheimer’s, Parkinson’s and Huntingdon’s diseases are not, therefore, usually broken down by the proteasome. These proteins can, however, be broken down by autophagy, and two papers in the current issue of Nature describe the effects of the deletion of autophagy genes in mice.

Komatsu et al and Hara et al produced transgenic mice lacking the Atg7 and Atg5 autophagy genes, respectively. In both studies, the genes were deleted in neurons only during late emroyonic development.

Significantly, both strains of mice developed symptoms of neurodegeneration, even in the absence of mutant (and potentially disease-causing) proteins. These studies suggest that one of the routine housekeeping duties of autophagy in nerve cells is to destroy aggregates of abnormally folded proteins found in the cytoplasm, thereby protecting the cells from degenerating.

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