Lysosomal Quality Control in Prion Diseases.

Prion diseases are transmissible, familial or sporadic. The prion protein (PrP), a normal cell surface glycoprotein, is ubiquitously expressed throughout the body. While loss of function of PrP does not elicit apparent phenotypes, generation of misfolded forms of the protein or its aberrant metabolic isoforms has been implicated in a number of neurodegenerative disorders such as scrapie, kuru, Creutzfeldt-Jakob disease, fatal familial insomnia, Gerstmann-Sträussler-Scheinker and bovine spongiform encephalopathy. These diseases are all phenotypically characterised by spongiform vacuolation of the adult brain, hence collectively termed as late-onset spongiform neurodegeneration. Misfolded form of PrP (PrPSc) and one of its abnormal metabolic isoforms (the transmembrane CtmPrP) are known to be disease-causing agents that lead to progressive loss of structure or function of neurons culminating in neuronal death. The aberrant forms of PrP utilise and manipulate the various intracellular quality control mechanisms during pathogenesis of these diseases. Amongst these, the lysosomal quality control machinery emerges as one of the primary targets exploited by the disease-causing isoforms of PrP. The autophagosomal-lysosomal degradation pathway is adversely affected in multiple ways in prion diseases and may hence be regarded as an important modulator of neurodegeneration. Some of the ESCRT pathway proteins have also been shown to be involved in the manifestation of disease phenotype. This review discusses the significance of the lysosomal quality control pathway in affecting transmissible and familial types of prion diseases.