Page 107 - AN-4-1

Advanced Neurology TDP-43 regulates IFN1 production

indicate that TDP43 facilitates TBK1 degradation through this study, co-expression of TDP43 with TBK1 in HEK-
autophagy. 293T cells significantly reduced the expression of IFN-α
and IFN-β, as well as the expression of ISG54 and ISG56.
4. Discussion These findings suggest a strong association between TDP43-

The ubiquitinated inclusions in neurons and glial cells are mediated neurodegeneration and IFN1 signaling. Notably,
one of the hallmark features of ALS and frontotemporal while co-expression of TDP43 with TBK1 decreased IRF7
lobe degeneration (FTD). These inclusions are primarily expression, it did not affect IRF3 levels.
composed of TDP43. 25,26 The motor neuron degeneration in TBK1 activation relies on phosphorylation at serine
ALS leads to muscle atrophy, paralysis, and ultimately death. 172 within its canonical kinase activation loop, which
32
The pathological inclusions observed in both ALS and FTD is crucial for the transcriptional activation of the IRF
patients consist of a 43 kDa aggregated TDP43 protein. family. Mutations in TBK1 underscore its importance
33
Emerging evidence indicates that TDP43 exhibits cellular in various human diseases, including ALS, FTD, normal
prion-like properties, which are thought to contribute to tension glaucoma (NTG), and pediatric herpes simplex
key characteristics of ALS. The cytoplasmic accumulation encephalitis (HSE). Gain-of-function mutations in TBK1
26
of misfolded, hyperphosphorylated TDP43 is considered a are linked to NTG, whereas loss-of-function mutations
critical factor in neurodegeneration, especially in ALS and lead to ALS/FTD or HSE, highlighting TBK1’s diverse
FTD pathogenesis. 27,28 Dysfunction or mutations in TBK1 roles in neuroinflammatory diseases and emphasizing its
have also been implicated in the development of ALS and significance in disease mechanisms. Previous studies
33
FTD, although TBK1’s specific role in neurodegeneration have shown that overexpression of TBK1 induces its
remains poorly understood. A recent study revealed autophosphorylation, activating the kinase. This activation
that the TBK1 p.G175S variant disrupts TBK1-mediated enables TBK1 to phosphorylate IRF3, a crucial protein in
NF-κB signaling pathway, leading to impaired autophagy the innate immune response pathway, which subsequently
and promoting the accumulation of TDP43 protein, which initiates the production of IFN1. 33-35 Consistently, this study
is implicated in neurodegenerative diseases such as ALS revealed that TBK1 promotes its own autophosphorylation
and FTD. The mutation hinders the proper degradation
of TDP43 through the autophagic process by disrupting and enhances IRF3 phosphorylation. Phosphorylation of
TBK1’s ability to activate NF-κB signaling. Furthermore, TBK1 is tightly regulated by phosphatases. For instance,
9
Xu et al. demonstrated that TBK1 haploinsufficient protein phosphatase 1B (PPM1B) binds to TBK1 and
29
(TBK1 ) mice exhibit hallmark ALS features, including dephosphorylates it at serine 172 following viral infection,
+/−
neuroinflammation, TDP43 aggregation, loss of axons, thereby terminating TBK1-mediated activation of
36
and degeneration of neurons. These findings suggest that IRF3. Similarly, the glucocorticoid dexamethasone has
TBK1 mutations or deficiencies influence TDP43 function, been shown to suppress TBK1 kinase activity, reducing
although the mechanisms underlying this interaction phosphorylation of both TBK1 and IRF3, effectively
remain unclear. In this study, it was demonstrated that inhibiting the signaling pathway crucial for innate immune
37
TDP43 overexpression impairs TBK1 function, providing responses, particularly against viral infections. In this
new insights into the relationship between these two study, co-expression of TDP43 with TBK1 led to decreased
proteins in ALS pathogenesis. TBK1 protein levels and reduced phosphorylation of TBK1
and IRF3, further supporting the regulatory role of TDP43
Metastasis-associated lung adenocarcinoma transcript-1 in TBK1-mediated signaling pathways.
can directly interact with TDP43 and suppress its cleavage.
Its reduction following viral infection has been shown The activation of TBK1 triggers the activation of
to enhance IRF3 activation and IFN1 production. In transcription factors IRF3 and IRF7, which is crucial for
30
THP-1 cells, overexpression of TDP43 activates cyclic GMP- initiating IFN1 production in reaction to viral infections.
AMP synthase (cGAS), subsequently leading to the release of As a master regulator of IFN1-dependent immune
31
inflammatory signals, such as NF-κB and IFN1. Moreover, responses, IRF7 interacts with N-myc and STAT interactor
in Prp-TDP43 Tg/+ mice, pathological TDP43 promotes the (NMI), which negatively regulate virus-induced IFN1
18
release of mitochondrial DNA (mtDNA) into the cytoplasm. production. IRF7 has been shown to stimulate the
This released mtDNA activates the cGAS/stimulator of production of IFN1 (including IFN-α and IFN-β) following
interferon genes (STING) signaling pathway, which is a key viral infection. 15,16 Studies utilizing IRF7-KO mice have
driver of innate immune responses. Interestingly, deletion demonstrated increased susceptibility to viral infections,
of STING abolishes the upregulation of IFN1 and NF-κB characterized by impaired production of IL-1β and IFN-β
in the spinal cord, highlighting the critical role of STING during endotoxin-induced septic shock or HSV-1 infection
31
in mediating TDP43-associated ALS/FTD pathology. In in mouse embryonic fibroblasts. 17,18,38 The strong induction

Volume 4 Issue 1 (2025) 101 doi: 10.36922/an.6272