Optineurin in amyotrophic lateral sclerosis: Multifunctional adaptor protein at the crossroads of different neuroprotective mechanisms. (July 2017)

• Record Type: Journal Article
• Authors: Markovinovic, Andrea; Cimbro, Raffaello; Ljutic, Tereza; Kriz, Jasna; Rogelj, Boris; Munitic, Ivana
• Is Part Of: Progress in neurobiology. Volume 154(2017:Jul.)
• Page Start: 1
• Page End: 20
• Publication Date: 2017-07
• Subjects: ABIN A20 binding and inhibitor of NF-κB -- AD Alzheimer's disease -- ALS amyotrophic lateral sclerosis -- Atg autophagy-related gene -- C9ORF72 chromosome 9 open reading frame 72 -- CC coiled-coil -- cIAP cellular inhibitor of apoptosis protein -- CYLD cylindromatosis -- DAMPs damage-associated molecular patterns -- FADD Fas-associated protein with death domain -- fALS familiar amyotrophic lateral sclerosis -- FasL Fas ligand -- FIP-2 adenovirus E3-14.7 K-interacting protein -- FTD frontotemporal dementia -- FUS fused in sarcoma -- HACE1 HECT domain and ankyrin repeat containing E3 ubiquitin protein ligase 1 -- HD Huntington's disease -- HGMB1 high-mobility group protein 1 -- Htt huntingtin -- IFN interferon -- IKK IκB kinase -- iNOS inducible nitric oxide synthase -- LC3 microtubule-associated proteins 1A/1B light chain 3 -- LIR LC3-interacting region -- LPS lipopolysaccharide -- LMN lower motor neuron -- LUBAC linear ubiquitin chain assembly complex -- MLKL mixed lineage kinase domain-like protein -- NAP1 NAK-associated protein 1 -- NDP-52 nuclear dot protein 52 -- NEMO NF-κB essential modulator -- NF-κB nuclear factor kappa-light-chain-enhancer of activated B cells -- NMD nonsense-mediated mRNA decay -- NRP NEMO-related protein -- NSC-34 neuroblastoma/spinal-cord cell line 34 -- PAMPs pathogen-associated molecular patterns -- PD Parkinson's disease -- PET positron emission tomography -- PINK1 PTEN-induced putative kinase 1 -- POAG primary-open angle glaucoma -- RIPK1 receptor interacting protein kinase 1 -- sALS sporadic amyotrophic lateral sclerosis -- SINTBAD similar to NAP1 TBK1 adaptor -- SOD1 superoxide dismutase 1 -- SQSTM1 sequestosome 1 -- TANK TRAF family member-associated NF-κB activator -- TAX1BP1 Tax-binding protein 1 -- TBK1 TANK-binding kinase 1 -- TDP-43 transactive response DNA binding protein of 43 kDa -- TFIIIA-intP transcription factor IIIA interacting protein -- TGF-β1 transforming growth factor beta 1 -- Th T cell helper -- TLR toll-like receptor -- TNF tumor necrosis factor -- TNF receptor-associated factor 1 -- TRAIL TNF-related apoptosis-inducing ligand -- TRAF TNF receptor associated factor -- UBAN ubiquitin-binding region of ABIN proteins and NEMO -- ULK1 Unc-51 like autophagy activating kinase 1 -- UMN upper motor neuron -- UPS ubiquitin-proteasome system -- ZF zinc finger; Amyotrophic lateral sclerosis -- Neurodegeneration -- Optineurin -- Autophagy -- Neuroinflammation -- Necroptosis; Neurobiology -- Periodicals; Neurology -- Periodicals; Neurology -- Periodicals; Neurobiologie -- Périodiques; 612.8
• DOI: 10.1016/j.pneurobio.2017.04.005
• Languages: English
• ISSNs: 0301-0082

Abstract

Highlights: Optineurin is a ubiquitin-binding adaptor protein whose mutations have been recently linked to ALS. The predominant disease mechanism for optineurin mutations in ALS patients is loss-of-function and/or haploinsufficiency. ALS-linked mutations in optineurin-interacting proteins, TBK1 and p62, suggest a common pathogenic pathway. Functional data argue that optineurin regulates the interconnected processes of autophagy, inflammation and necroptosis. We propose that when optineurin is limiting several optineurin-mediated neuroprotective events could fail at the same time. Abstract: 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.