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.
Highlights
Age-associated neurodegenerative diseases that affect central nervous system (CNS) neurons are typically sporadic with only a small fraction traceable to inherited mutations in susceptibility genes
Recent findings have indicated that mutant HTT (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, plausibly promoting neuropathology within proximal neuronal populations and between neurons that are connected within neural circuits
Summary
Age-associated neurodegenerative diseases that affect central nervous system (CNS) neurons are typically sporadic with only a small fraction traceable to inherited mutations in susceptibility genes. Accumulating evidence over the past decade has suggested that these extracellular secreted pathological entities could propagate disease when taken up by neighboring neurons and glia As these proteins largely exist cytoplasmically upon translation and lack recognizable leader or signal sequences for targeting to the classical secretory pathway [62,63], their mode of secretion is necessarily unconventional [64,65,66], occurring largely via the generation of extracellular vesicles (EVs) such as exosomes [67,68].
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