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Advanced Neurology TDP-43 regulates IFN1 production

1. Introduction as transcription factors for IFN1 (specifically IFN-α
and IFN-β) and associated cytokines. 13-15 In humans
Amyotrophic lateral sclerosis (ALS) is a fatal and mice, interferon-producing cells (IPCs) comprise
neurodegenerative disease characterized by the 0.2% – 0.8% of peripheral blood mononuclear cells and
progressive degeneration of upper and lower motor selectively express toll-like receptor (TLR) 7 and toll-
neurons, leading to muscle weakness, atrophy, paralysis, like receptor 9. On viral stimulation, IPCs secrete large
1,2
and ultimately respiratory failure. A hallmark of quantities of IFN1, which activate B-cells, natural killer
ALS is the abnormal cytoplasmic mislocalization cells, T-cells, and myeloid dendritic cells during antiviral
and aggregation of TAR DNA-binding protein 43 immune responses. Although IRF3 and IRF7 share
16
(TDP43), observed in over 90% of ALS cases. TDP43, structural and functional similarities, their roles are
1
a ubiquitously expressed protein, plays a crucial distinct and essential. IRF7, a critical regulator of IFN1-
role in maintaining cellular survival under normal dependent immune responses, plays a more prominent
physiological conditions. Studies have shown that role than IRF3 in systemic IFN induction. Studies with
TDP43 disrupts RNA metabolism, endocytosis, the IRF7-deficient (IRF7 ) mice have demonstrated that
−/−
ubiquitin-proteasome system (UPS), and mitochondrial IRF7 is indispensable for inducing IFN-α/β expression.
function. Furthermore, autophagy-related proteins,
3-6
such as light chain 3 (LC3) and p62, have been found These mice show a significant reduction in serum IFN
levels and heightened susceptibility to viral infections,
to colocalize with TDP43 aggregates, and TDP43 emphasizing the importance of IRF7 in innate and
downregulation reduces LC3 and p62 levels, indicating adaptive immunities. 16,17 While IRF3 is ubiquitously
7,8
a reciprocal regulatory relationship between TDP43 and
autophagy. Recent findings suggest that TANK-binding expressed across various cell types, IRF7 is highly
kinase 1 (TBK1) overexpression promotes the autophagic expressed in plasmacytoid dendritic cells. Despite this,
IRF7 remains essential for regulating IFN1 production.
18
degradation of endogenous TDP43. In addition to
9
TBK1, other ALS-associated genes, such as ubiquilin-2 TBK1 has been widely studied for its role in interacting
(UBQLN2), C9orf72, and profilin-1 (PFN1), have also with autophagy receptors, including p62 and optineurin,
been implicated in regulating TDP43 dynamics. 10-12 which are essential in regulating selective autophagy. By
phosphorylating these receptors, TBK1 enables the targeting
Most ALS cases are sporadic, with TBK1 mutations
identified as a significant contributing factor in of damaged proteins and organelles to autophagosomes for
degradation, serving as a crucial component in the cellular
approximately 4% of ALS and frontotemporal dementia
(FTD) patients. FTD refers to a group of neurological protein degradation pathway. Autophagy, a vital cellular
9
disorders caused by neurodegeneration in the brain, mechanism for eliminating toxic protein aggregates and
leading to shrinkage of these regions. This condition unwanted materials, is often dysregulated in ALS/FTD,
implicating its role in disease progression. For instance,
can impact behavior, personality, and motor functions.
TBK1, an innate immune kinase, activates interferon TBK1 mutations result in the accumulation of autophagic
regulatory factors (IRF) including IRF3 and IRF7, markers LC3 and p62 (SQSTM1), impairing autophagic
13,19-23
which, in turn, promote the production of type I induction. Similarly, mutations in UBQLN2, another
ALS-associated gene, impair TBK1’s binding to p62,
interferons (IFN1). In TBK1 mice, pathological 15
Δ/Δ
findings include hyperkeratosis, necrosis, hyperplasia, further disrupting autophagic induction. TBK1-deficient
inflammatory cell infiltration, and edema in the skin at mice show elevated LC3 and p62 levels, reinforcing the link
14,15
2 weeks of age. In comparison to TBK1 and TBK1 between TBK1 dysfunction and impaired autophagy.
+/Δ
+/−
mice, these mice show heightened vulnerability to In addition, mutations in p62 are linked to ALS/FTD,
emphasizing that autophagic dysfunction plays a critical
lipopolysaccharide (LPS)-induced lethality at 3 months,
marked by elevated levels of pro-inflammatory role in the pathogenesis of neurodegeneration.
cytokines in serum, including tumor necrosis factor- The present study explored the effect of TDP43 on
alpha, interleukin-6 (IL-6), granulocyte-macrophage TBK1, revealing that TDP43 overexpression significantly
colony-stimulating factor (GM-CSF), and keratinocyte reduced TBK1 expression, accompanied by decreased
chemoattractant. The heightened immune response and IRF7 and IFN1 production. However, overexpression
cytokine production in TBK1 mice are attributed to an of IRF7 alleviated these reductions. These findings
Δ/Δ
expanded circulating mononuclear cell compartments indicate that TDP43 negatively regulates TBK1-mediated
and elevated immune cell activation. 13,14 On activation, IFN1 production through IRF7, and disruption of
TBK1 facilitates IRF3 and IRF7 homodimerization this pathway may be a key factor in TDP43-associated
and nuclear translocation, enabling them to function neurodegeneration.

Volume 4 Issue 1 (2025) 95 doi: 10.36922/an.6272