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JOURNAL ARTICLE
REVIEW
Optineurin in amyotrophic lateral sclerosis: Multifunctional adaptor protein at the crossroads of different neuroprotective mechanisms.
Progress in Neurobiology 2017 July
When optineurin mutations showed up on the amyotrophic lateral sclerosis (ALS) landscape in 2010, they differed from most other ALS-causing genes. They seemed to act by loss- rather than gain-of-function, and it was unclear how a polyubiquitin-binding adaptor protein, which was proposed to regulate a variety of cellular functions including cell signaling and vesicle trafficking, could mediate neuroprotection. This review discusses the considerable progress that has been made since then. A large number of mutations in optineurin and optineurin-interacting proteins TANK-binding kinase (TBK1) and p62/SQSTM-1 have been found in the ALS patients, suggesting a common neuroprotective pathway. Moreover, functional studies of the ALS-causing optineurin mutations and the recently established optineurin ubiquitin-binding deficient and knockout mouse models helped identify three major mechanisms likely to mediate neuroprotection: regulation of autophagy, mitigation of (chronic) inflammatory signaling, and blockade of necroptosis. These three processes crosstalk, and require multiple levels of control, many of which can be mediated by optineurin. Based on the role of optineurin in multiple processes and the unexpected finding that targeted optineurin deletion in microglia and oligodendrocytes ultimately leads to the same phenotype of axonal degeneration despite different initial defects, we propose that the failure of the weakest link in the optineurin neuroprotective network is sufficient to disturb homeostasis and set-off the domino effect that could ultimately lead to neurodegeneration.
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