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Written byNovember
Frontotemporal dementia (FTD) and Amyotrophic lateral sclerosis (ALS).
IT IS RELATED TO REPEATED AMPLIFICATION OF THE C9orf72 GENE AND MUTATION OF THE TBK1 (TANK-binding kinase 1) GENE [1].
。 Studies have found that some patients have repeated amplification of C9orf72 and mutations in TBK1 at the same time, and these patients will have an earlier age of onset and a faster course of disease [2-3].
Thus, TBK1 may regulate the occurrence and progression
of C9orf72-related FTD-ALS.
To study the role of these two genes in FTD-ALS, the team of Leonard Petrucelli/Yong-Jie Zhang of Mayo Clinic (first author: Dr.
Wei Shao) published a paper in Science Two FTD-ALS genes converge on the endosomal pathway to induce TDP-43 pathology and degeneration, where TBK1 is phosphorylated upon repeated polymerization in C9orf72 and subsequently wrapped into aggregates (Aggregates) leads to loss of TBK1 activity, which eventually leads to neurodegeneration
.
The most important feature of frontotemporal dementia and lateral sclerosis is the formation of protein aggregates, especially TDP-43
.
The formation of aggregates means that protein clearance is impaired, and these FTD-ALS-associated genes influence protein homeostasis
.
To detect the effect of TBK1 mutations and GC repeats in C9orf72 on FTD-ALS, the authors used an adeno-associated virus-based mouse model of C9orf72-(G4C2)149 in which GC reached 149 replicates in C9orf72 to determine whether repeated amplification of C9orf72 affected the phosphorylation status
of TBK1 。 The authors found that total TBK1 levels in cerebral cortical lysate were comparable in C9orf72-(G4C2)149 mice and C9orf72-(G4C2)2 controls, but pTBK1 levels increased
significantly in C9orf72-(G4C2)149 mice.
In addition, C9orf72-(G4C2)149 is co-localized in
aggregates with pTBK1.
Thus, C9orf72-(G4C2)149 is able to trigger phosphorylation and abnormal aggregation of TBK1 in the mouse brain (Figure 1).
Fig.
1 TBK1 increases phosphorylation after repeated GC amplification in C9orf72 and is isolated into inclusions
.
The authors believe that aggregates of C9orf72-(G4C2)149 will isolate pTBK1, and TBK1 has no way to regulate the function of autophagy clearance of aggregates [4]
。 The authors found that expression of wild-type TBK1 in aggregate-expressed cells led to a significant increase in
phosphorylation of the autophagy receptor protein p62.
However, when overexpressing some loss-of-function mutant TBK1 with reduced autophosphorylation activity, aggregates do not decrease
.
Therefore, TBK1 is isolated by aggregates, which will impair the activity of TBK1 and exacerbate neuronal defects
.
By simulating the double mutation by simultaneously typing in mice with TBK1 mutants and aggregates expressing them at the same time, the authors found that it led to neurodegenerative disease features such as loss of total brain weight and loss of cortical neurons
.
The loss of TBK1 impairs the endosome maturation process of human motor neurons [5].
The authors wondered whether the isolation of TBK1 also affected endosomal maturation signaling pathways
in vivo.
The authors found that early endosomes in aggregate-expressing mouse cortex exhibited an enlarged phenotype, while Rab7-positive late endosomes also showed abnormalities
.
In addition, the authors found that abnormalities in endosomal maturation signaling pathways lead to pathological features
of TDP-43 in cortical neurons.
This establishes a link between
aggregates, endosome defects, and the characteristics of TDP-43 cases.
Overall, the authors' work found that TBK1 increases phosphorylation levels during multimerization of C9orf72 repeats and is isolated into aggregates, leading to loss of TBK1 activity, and increased aggregates inhibit endosomal pathways to induce TDP-43 aggregation, which in turn leads to neurodegeneration
.
The work combines the interaction between C9orf72, TBK1, and TDP-43 to connect three different aspects of FTD-ALS into a coherent pathway
.
At the same time, Science issued a special review: A perturbed network in neurodegeneration
.
To date, more than 20 genes that appear to be unrelated to each other have been identified as pathogenic genes or important regulators of ALS-FTD; This study establishes the interaction and influence of three important genes of ALS-FTD, C9orf72, TBK1 and TDP-43 in the endocytic-lysosomal pathway, which brings conceptual innovation to our understanding of the pathogenic mechanism of ALS-FTD and suggests new therapeutic targets for diseases
.
Original link:
http://doi.
org/10.
1126/science.
abq7860
Pattern maker: Eleven
References
1.
European Centre for Disease Prevention and Control, Epidemiological update: Monkeypox outbreak (ECDC, 2022); epidemiological-update-monkeypox-outbreak.
2.
Z.
Jezek, B.
Grab, K.
M.
Paluku, M.
V.
Szczeniowski, Trop.
Geogr.
Med.
40, 73–83 (1988).
3.
E.
M.
Beer, V.
B.
Rao, PLOS Negl.
Trop.
Dis.
13, e0007791 (2019)
4.
18.
J.
A.
Oakes, M.
C.
Davies, M.
O.
Collins, Mol.
Brain 10, 5 (2017)
5.
J.
Hao et al.
, bioRxiv 2021.
10.
11.
464011 [Preprint] (2021).
https://doi.
org/10.
1101/2021.
10.
11.
464011.
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