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Lysosomal Quality Control in Prion Diseases

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Abstract

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.

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Abbreviations

AD:

Alzheimer’s disease

BSE:

Bovine spongiform encephalopathy

CJD:

Creutzfeldt-Jakob disease

ECR:

Endosomal recycling compartment

ERAD:

ER-associated degradation

ESCRT:

Endosomal sorting complex required for transport

FFI:

Fatal familial insomnia

GPI:

Glycosylphosphatidylinositol

GSS:

Gerstmann-Straussler-Scheinker syndrome

HD:

Huntington’s disease

MGRN1:

Mahogunin RING Finger1

MVB:

Multivesicular body

PD:

Parkinson’s disease

PIPLC:

Phosphatidylinositol-specific phospholipase C

PrP:

Prion

RESET:

Rapid ER stress-induced export

sCJD:

Sporadic Creutzfeldt-Jakob disease

TGN:

Trans-Golgi network

UPS:

Ubiquitin proteasomal system

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Acknowledgements

This work was supported by the “Integrative Biology on Omics Platform Project”, intramural funding of the Department of Atomic Energy (DAE), Government of India.

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    Priyanka Majumder & Oishee Chakrabarti

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Majumder, P., Chakrabarti, O. Lysosomal Quality Control in Prion Diseases. Mol Neurobiol 55, 2631–2644 (2018). https://doi.org/10.1007/s12035-017-0512-8

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