Whole-genome sequencing reveals important role for TBK1 and OPTN mutations in frontotemporal lobar degeneration without motor neuron disease

Abstract

Frontotemporal lobar degeneration with TAR DNA binding protein 43 inclusions (FTLD-TDP) is the most common pathology associated with frontotemporal dementia (FTD). Repeat expansions in chromosome 9 open reading frame 72 (C9ORF72) and mutations in progranulin (GRN) are the major known genetic causes of FTLD-TDP; however, the genetic etiology in the majority of FTLD-TDP remains unexplained. In this study, we performed whole-genome sequencing in 104 pathologically confirmed FTLD-TDP patients from the Mayo Clinic brain bank negative for C9ORF72 and GRN mutations and report on the contribution of rare single nucleotide and copy-number variants in 21 known neurodegenerative disease genes. Interestingly, we identified 5 patients (4.8%) with variants in optineurin (OPTN) and TANK-binding kinase 1 (TBK1) that are predicted to be highly pathogenic, including two double mutants. Case A was a compound heterozygote for mutations in OPTN, carrying the p.Q235* nonsense and p.A481V missense mutation in trans, while case B carried a deletion of OPTN exons 13–15 (p.Gly538Glufs*27) and a loss-of-function mutation (p.Arg117*) in TBK1. Cases C–E carried heterozygous missense mutations in TBK1, including the p.Glu696Lys mutation which was previously reported in two amyotrophic lateral sclerosis (ALS) patients and is located in the OPTN binding domain. Quantitative mRNA expression and protein analysis in cerebellar tissue showed a striking reduction of OPTN and/or TBK1 expression in 4 out of 5 patients supporting pathogenicity in these specific patients and suggesting a loss-of-function disease mechanism. Importantly, neuropathologic examination showed FTLD-TDP type A in the absence of motor neuron disease in 3 pathogenic mutation carriers. In conclusion, we highlight TBK1 as an important cause of pure FTLD-TDP, identify the first OPTN mutations in FTLD-TDP, and suggest a potential oligogenic basis for at least a subset of FTLD-TDP patients. Our data further adds to the growing body of evidence linking ALS and FTD and suggests a key role for the OPTN/TBK1 pathway in these diseases.

Dynamic recruitment and activation of ALS-associated TBK1 with its target optineurin are required for efficient mitophagy

“…Another study linked loss-of-function TBK1 mutations to both ALS and FTD (21). Finally, mutations in both TBK1 and OPTN are causal for both ALS and glaucoma (20,31). In this study, we observed that the ALS-associated mutants TBK1-E696K, OPTN-E478G, and OPTN-Q398X all interfere with efficient autophagic engulfment of damaged mitochondria.…”

“…Thus, the rate at which acutely damaged mitochondria are engulfed by autophagosomes may potently affect cellular homeostasis, with delays leading to toxic cellular insult. Consistent with this possibility, mutations in OPTN cause neurodegeneration, including both ALS and glaucoma, whereas TBK1 mutations also result in ALS and are implicated in frontotemporal dementia (FTD) (17)(18)(19)(20)(21)(22).…”

“…In the past several years, multiple mutations in both OPTN and TBK1 have been identified in patients with ALS and FTD (17)(18)(19)(20)(21)(22). We therefore examined whether these disease-associated mutations interfere with efficient mitophagy.…”

Microglia and C9orf72 in neuroinflammation and ALS and frontotemporal dementia

“…Interestingly, in a small cohort of patients with the rare combination of MS and ALS, approximately 80% carried a hexanucleotide repeat expansion in C9orf72 (128), suggesting these patients may have hyperactive immune responses to myelin antigens. Likewise, the recent identification of loss-of-function mutations in TBK1, a well-characterized regulator of innate immunity, as a cause of ALS/FTD (18,129,130) further reinforces the concept that immune dysregulation might be a characteristic feature of the disease. Despite the strong case for a connection between ALS/FTD and autoimmunity, there is also convincing evidence against the idea that ALS is itself a classical autoimmune condition, given that administration of immunosuppressive drugs including corticosteroids, azathioprine, and cyclophosphamide (alone or in combination), as well as plasmapheresis or intravenous Igs (IVIGs), has failed to alter the progression of the disease (131)(132)(133)(134)(135)(136)(137).…”

OPTN 691_692insAG is a founder mutation causing recessive ALS and increased risk in heterozygotes

“…33 Another study suggested an additional more complex mode of inheritance for OPTN in neurodegenerative disease: a compound heterozygosity either within OPTN or together with the TBK1 gene. 34 We showed for the first time that OPTN 691_692insAG mutation is associated with AR ALS. In addition, the remarkable differences in frequencies of mutation carriage between MJ-ALS and MJ controls, and the replication of these results in AJ, with significantly increased risk for ALS in heterozygous carriers, strongly suggest that this mutation also has a dominant effect on ALS in the same populations.…”