TBK1: a new player in ALS linking autophagy and neuroinflammation

Abstract

Amyotrophic lateral sclerosis (ALS) is an adult-onset neurodegenerative disorder affecting motor neurons, resulting in progressive muscle weakness and death by respiratory failure. Protein and RNA aggregates are a hallmark of ALS pathology and are thought to contribute to ALS by impairing axonal transport. Mutations in several genes known to contribute to ALS result in deposition of their protein products as aggregates; these include TARDBP, C9ORF72, and SOD1. In motor neurons, this can disrupt transport of mitochondria to areas of metabolic need, resulting in damage to cells and can elicit a neuroinflammatory response leading to further neuronal damage. Recently, eight independent human genetics studies have uncovered a link between TANK-binding kinase 1 (TBK1) mutations and ALS. TBK1 belongs to the IKK-kinase family of kinases that are involved in innate immunity signaling pathways; specifically, TBK1 is an inducer of type-1 interferons. TBK1 also has a major role in autophagy and mitophagy, chiefly the phosphorylation of autophagy adaptors. Several other ALS genes are also involved in autophagy, including p62 and OPTN. TBK1 is required for efficient cargo recruitment in autophagy; mutations in TBK1 may result in impaired autophagy and contribute to the accumulation of protein aggregates and ALS pathology. In this review, we focus on the role of TBK1 in autophagy and the contributions of this process to the pathophysiology of ALS.

Keywords: ALS; Amyotrophic lateral sclerosis; Autophagy; FTD; Frontotemporal dementia; Mitophagy; Motor neuron disease; Neuroinflammation; Signaling; TBK1.

Fig. 1

a Primary structure of TBK1. TBK1 is 729 amino acids in length and comprises four main domains: a kinase domain (KD), ubiquitin-like domain (ULD) and two coiled-coil domains (CCD1 and CCD2). Locations of TBK1 mutations associated with ALS and ALS-FTD are indicated by vertical lines: Black – frame shift mutations, orange – nonsense mutations, green – Missense mutations, blue – in-frame deletions, purple – splice mutations and yellow - insertion mutations. b Tertiary structure of TBK1. The region highlighted in red represents the kinase domain, the turquoise region represents the ubiquitin-like domain and the yellow region represents coiled-coil domain 1. Coiled-coil domain 2 is not shown in this model. Diagram produced in PyMOL using crystal structure data published by Larabi et al. 2013 [40] accessed via protein databank (accession number: 4IWO). (RCSB Protein Data Bank, 2016)

Fig. 2

Frequency of different types of ALS and FTD-associated TBK1 mutations. Summary of data compiled in Additional file 1: Table S1

Fig. 3

Autophagolysosome formation and maturation. Autophagy involves the formation of an isolation membrane. This membrane undergoes elongation, forming a phagophore and a portion of the cytoplasm is separated to form an autophagosome. This involves the ULK1-ATG13-FIP200, Beclin1-PI3K CIII and Atg5-Atg12-Atg16 complexes The autophagosome fuses with a lysosome to form an autophagolysosome, allowing digestive enzymes to degrade any material in the vesicle. TBK1 binds and phosphorylates autophagy receptors OPTN and p62; they bind to ubiquitin residues on target cargo and to LC3-II. This enhances the ability of the receptors to bind ubiquitinated residues on target cargo and LC3-II. This all allows ubiquitinated cargo to be recruited to the phagophore for degradation; the receptors act as adaptors that link cargo to autophagic machinery