Appropriating microbial catabolism: a proposal to treat and prevent neurodegeneration

Intraneuronal, largely proteinaceous aggregates accumulate in all major neurodegenerative disorders. Lysosomal degradation of proteinaceous and other material declines early in such diseases. This suggests that intraneuronal aggregates consist of material which is normally broken down in the lysosome and thus accumulates when lysosomal degradation fails. This is plausible even though those aggregates are generally non-lysosomal, because lysosomal uptake may be affected. Thus, restoring lysosomal function might eliminate them--and without increasing the concentration of the soluble monomers or oligomers of which they are formed. This approach is therefore unlikely to be harmful and may well be beneficial. How might lysosomes be rejuvenated? Since lysosomal dysfunction is likely to be caused by intralysosomal material that is resistant to lysosomal degradation, normal function might be recovered by augmenting that function to cause the toxin to be degraded. Here, I describe how such augmentation might be achieved with microbial enzymes. Soil microbes display astonishing catabolic diversity, something exploited for decades in the bioremediation industry. Environments enriched in human remains impose selective pressure on the microbial population to evolve the ability to degrade any recalcitrant, energy-rich human material. Thus, microbes may exist that can degrade these lysosomal toxins. If so, it should be possible to isolate the genes responsible and modify them for therapeutic activity in the mammalian lysosome.