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Cells 2018, 7(6), 59; https://doi.org/10.3390/cells7060059

Unconventional Secretion and Intercellular Transfer of Mutant Huntingtin

1
Department of Biochemistry, Yong Loo Lin School of Medicine, 117597 Singapore, Singapore
2
NUS Graduate School for Integrative Sciences and Engineering, 117456 Singapore, Singapore
Received: 23 May 2018 / Revised: 8 June 2018 / Accepted: 12 June 2018 / Published: 14 June 2018
(This article belongs to the Special Issue Unconventional Protein Secretion in Development and Disease)
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Abstract

The mechanism of intercellular transmission of pathological agents in neurodegenerative diseases has received much recent attention. Huntington’s disease (HD) is caused by a monogenic mutation in the gene encoding Huntingtin (HTT). Mutant HTT (mHTT) harbors a CAG repeat extension which encodes an abnormally long polyglutamine (polyQ) repeat at HTT’s N-terminus. Neuronal pathology in HD is largely due to the toxic gain-of-function by mHTT and its proteolytic products, which forms both nuclear and cytoplasmic aggregates that perturb nuclear gene transcription, RNA splicing and transport as well cellular membrane dynamics. The neuropathological effects of mHTT have been conventionally thought to be cell-autonomous in nature. Recent findings have, however, indicated that mHTT could be secreted by neurons, or transmitted from one neuronal cell to another via different modes of unconventional secretion, as well as via tunneling nanotubes (TNTs). These modes of transmission allow the intercellular spread of mHTT and its aggregates, thus plausibly promoting neuropathology within proximal neuronal populations and between neurons that are connected within neural circuits. Here, the various possible modes for mHTT’s neuronal cell exit and intercellular transmission are discussed. View Full-Text
Keywords: Huntingtin (HTT); Huntington’s disease (HD); membrane traffic; polyglutamine (polyQ) tract; tunneling nanotube (TNT); unconventional secretion Huntingtin (HTT); Huntington’s disease (HD); membrane traffic; polyglutamine (polyQ) tract; tunneling nanotube (TNT); unconventional secretion
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Tang, B.L. Unconventional Secretion and Intercellular Transfer of Mutant Huntingtin. Cells 2018, 7, 59.

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