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Written by ︱ Yin Peng editor ︱ Sizhen Wang Neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD) and Alzheimer's disease are caused by mistakes caused by the accumulation of folded proteins
.
SQSTM1 (Sequestosome 1), also known as p62, is a multifunctional ubiquitin-binding protein involved in the degradation of two proteins, the ubiquitin-proteasome system and the autophagy-lysosome system, and can selectively remove misfolded proteins
.
Therefore, its impaired function is closely related to the accumulation of misfolded proteins and neurodegenerative diseases
.
TDP-43 (TAR DNA-binding protein 43) is a causative protein of neurodegenerative diseases
.
Under normal circumstances, it is distributed in the nucleus of nerve cells and is involved in important processes such as gene transcription inhibition and RNA precursor splicing [1,2]
.
When the TDP-43 gene is abnormally mutated and in some neuropathological conditions, TDP-43 in the nucleus is transferred to the cytoplasm, causing neurotoxicity [3,4]
.
However, in the mouse model, the vast majority of TDP-43 still accumulates in the nucleus, which cannot fully simulate the pathological characteristics of TDP-43 accumulation in the cytoplasm in the brain of patients
.
Based on the significant differences between large animals and mice in simulating important pathological changes in neurodegenerative diseases, Li Xiaojiang's team expressed mutant TDP-43 (M337V) in primates and mice substantia nigra in 2019, and found that TDP-43 Monkeys show pathological features similar to the accumulation of cytoplasmic TDP-43 in patients, which is distinct from the accumulation of TDP-43 in the nucleus observed in mouse models [5], which is only specifically expressed in higher animals such as humans and monkeys The hydrolase caspase-4 cleaves TDP-43, so that the TDP-43 fragment product lacking the nuclear localization signal is transferred to the cytoplasm [5]
.
On December 22, 2021, the team of Li Xiaojiang from the Guangdong-Hong Kong-Macao Institute of Central Nervous Regeneration, Jinan University published a study entitled "SQSTM1 mediated clearance of cytoplasmic mutant TARDBP/TDP-43 in the monkey brain" in the journal Autophagy.
research paper
.
By comparing the TDP-43 mouse model, this study found that the SQSTM1 gene in non-human primates is specifically regulated by TDP-43 and its role in clearing cytoplasmic aggregates, once again demonstrating the use of non-human primates.
Importance of animal-like models to study neurodegenerative diseases
.
Researcher Yin Peng of Jinan University is the first author and co-corresponding author, and Professor Li Xiaojiang is the corresponding author of the article
.
In this paper, the authors firstly used viral vector-mediated expression of mutant TDP-43 (M337V) in cynomolgus monkey and mouse model cortical tissues.
Using fluorescent staining, it was found that TDP-43 was expressed as cytoplasmic aggregates in the monkey model.
form, and co-localized signal with SQSTM1 protein can be seen, which is similar to the pathological characteristics of diseases such as ALS and FTLD (Fig.
1A)
.
In addition, TDP-43 in the cytoplasm can specifically promote the instability of primate SQSTM1 (p62) mRNA (Fig.
1B), resulting in decreased SQSTM1 protein expression and impaired autophagic clearance (Fig.
1C), but this phenomenon did not occur in the mouse model
.
Figure 1 In the mutant TDP-43 primate monkey model, but not the mouse model, the cytoplasmic TDP-43 product can promote the instability of SQSTM1 mRNA, resulting in abnormal autophagy function
.
(Source: Yin P, et al.
, Autophagy, 2021) The 3' untranslated region (3' UTR) of mRNA is closely related to post-transcriptional gene expression and is important for biological processes such as mRNA stability and subcellular localization regulation [6,7]
.
By comparing the sequences of the 3'UTR region of SQSTM1 mRNA in humans, cynomolgus monkeys and mice, the authors found that in the 3'UTR region of primates (human and monkey), SQSTM1 mRNA has a longer (TG)n repeat sequence , while in mice, this repeat is only four (TG) repeats (Fig.
2A)
.
Therefore, the authors firstly used RNA immunoprecipitation (Fig.
2B, C) in parallel with RIP-Seq sequencing technology, and found that the expression of TDP-43 cytoplasmic fragment can specifically bind to the 3'UTR region of human SQSTM1 mRNA (Fig.
2D, E ), thereby promoting the degradation of primate SQSTM1 mRNA
.
However, in mice, the 3'UTR region of SQSTM1 lacks longer (TG)n repeats and is not bound by TDP-43, so there is no change in the expression level of SQSTM1
.
Figure 2 Longer (TG)n repeats in the 3'UTR region of primate SQSTM1 bind TDP-43, while short (TG)n repeats in mice do not
.
(Source: Yin P, et al.
, Autophagy, 2021) Next, the authors verified the clearance of TDP-43 aggregates by SQSTM1-mediated abnormal autophagy function
.
It was found that correcting the expression level of SQSTM1, as well as activating the autophagy-regulated pathway, both promoted the clearance of fragmented TDP-43 cytoplasmic aggregates (Fig.
3A,B)
.
Moreover, when SQSTM1 mediated by viral vector is expressed in the mutant TDP-43 model monkey brain, it can restore the autophagic clearance function and promote the reduction of TDP-43 fragmented and aggregated products, thus explaining the function in ALS/FTLD and other disease processes.
The essential role of sexual SQSTM1 in clearing misfolded proteins (Fig.
3C,D)
.
Figure 3 Primate-specific caspase-4 cleaves TDP-43, causing it to accumulate in the cytoplasm and cause cytotoxicity; SQSTM1 promotes the clearance of TDP-43 aggregates
.
(Source: Yin P, et al.
, Autophagy, 2021) The conclusion and discussion, inspiration and prospect of the article are combined with the author's previous report that the hydrolase caspase-4, which is specifically expressed in higher animals such as humans and monkeys, can cleave TDP-43 The TDP-43 fragment product lacking the nuclear localization signal is transferred to the cytoplasm [5]
.
This finding once again proves that the mechanism of ALS pathology is different between non-human primate models and mouse models.
The use of non-human primate models can better study the accumulation and neurotoxicity of TDP-43 in the cytoplasm ( Figure 3E)
.
In recent years, Li Xiaojiang's team found that pigs [8, 9] and monkey models [10, 11] can better simulate the typical pathological changes of neurodegenerative diseases, and some pathogenic related proteins or gene sequences only exist in large animals
.
The study of the TDP-43 monkey model further confirms the need to use large animal and non-human primate models to more accurately reveal the molecular mechanisms of neurodegenerative diseases and find effective treatments
.
Although the expression of mutant TDP-43 in primate cells can be used to study the pathological mechanism of cytoplasmic aggregates, overexpression of TDP-43 is often cytotoxic and cannot reflect the loss of normal TDP-43 in the nucleus.
Toxicity hypothesis, it is necessary to genetically edit endogenous TDP-43 to produce a mutant protein to better describe the neurotoxicity of mutant TDP-43
.
In addition, with the increasing application of large animal models in basic medicine, especially neuroscience research, the shortage of non-human primate monkey resources and its many limitations in feeding, maintenance and operation, researchers need to learn from monkey models.
The discovery of new mechanisms has led to the development and modification of mouse models to better mimic the pathological phenomena of the disease
.
Link to the original text: https://doi.
org/10.
1080/15548627.
2021.
2013653 Group photo of Li Xiaojiang's laboratory: Researcher Yin Peng (third from left) is the first author and co-corresponding author, Professor Li Xiaojiang (fifth from left) is the corresponding author of the article, and Other major contributors
.
(Photo provided by: Li Xiaojiang Laboratory) Jinan University Guo Xiangyu (third from right), associate researcher Li Bang (first from right), etc.
also participated in the research of this project
.
Researcher Wang Lu from the Imaging Center of the First Affiliated Hospital of Jinan University has made important contributions to monkey imaging observations
.
Professor Li Shihua from Jinan University (sixth from left) is also the co-corresponding author of the article
.
This study was funded by the Guangdong Provincial Department of Science and Technology, the National Key R&D Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, and the Guangdong Provincial Key Laboratory Platform for Non-Human Primate Model Research
.
Selected Previous Articles【1】Nat Neurosci︱Cao Peng’s lab discovered the important function of pain perception in the struggle for survival among species【2】Neurosci Bull︱Tongli’s research group revealed that dopaminergic neurons in the VTA-PrL neural pathway are in the rat Sevoflurane plays a wake-promoting effect under general anesthesia 【3】Nat Aging︱New discovery in Alzheimer's disease: a regulatory mechanism of bone marrow-derived macrophages independent of TREM2 pathway 【4】Sci Transl Med︱monoaminergic New evidence of delayed onset of antidepressant drugs: hippocampal cAMP modulates HCN channel function and then affects mouse behavior and memory [5] Nat Methods︱Peng Hanchuan's research group developed cross-modal brain registration technology for brain atlas construction and single-cell accuracy full scale Brain mapping research provides important support [6] Nat Commun︱ astrocytes inhibit the infiltration of peripheral macrophages in non-human primate cerebral ischemia injury [7] Cereb Cortex | Acquired multimodal neuroimaging features【8】Neurosci Bull︱Li Yunqing’s group revealed that neuroplastic changes in the anterior cingulate correlate with hyperalgesia and anxiety in chronic pancreatitis【9】Neuron︱Cao Peng’s laboratory found repetitive stereotyped behaviors The closed-loop neural mechanism of [10] EMBO Rep｜Kang Jiuhong's research group discovered a new mechanism of lncRNA SOX1-OT regulating human ESC neurogenesis Recommended for high-quality scientific research training courses [1] Common experimental paradigm for cognitive control and executive function [2] Single cell Sequencing and Spatial Transcriptomics Data Analysis Symposium Book Donation Event [1] Book Donation︱ Oxford Science Series "Brain" - Insomnia, Anxiety, Do You Really Know Your Brain? References (swipe up and down to view) [1] Rethinking ALS: the FUS about TDP-43.
Cell 136:1001–1004.
[2] TAR DNA-binding protein 43 in neurodegenerative disease.
Nat Rev Neurol 6:211–220.
[ 3] TDP-43 in familial and sporadic frontotem -poral lobar degeneration with ubiquitin inclusions.
Am J Pathol 171:
.
SQSTM1 (Sequestosome 1), also known as p62, is a multifunctional ubiquitin-binding protein involved in the degradation of two proteins, the ubiquitin-proteasome system and the autophagy-lysosome system, and can selectively remove misfolded proteins
.
Therefore, its impaired function is closely related to the accumulation of misfolded proteins and neurodegenerative diseases
.
TDP-43 (TAR DNA-binding protein 43) is a causative protein of neurodegenerative diseases
.
Under normal circumstances, it is distributed in the nucleus of nerve cells and is involved in important processes such as gene transcription inhibition and RNA precursor splicing [1,2]
.
When the TDP-43 gene is abnormally mutated and in some neuropathological conditions, TDP-43 in the nucleus is transferred to the cytoplasm, causing neurotoxicity [3,4]
.
However, in the mouse model, the vast majority of TDP-43 still accumulates in the nucleus, which cannot fully simulate the pathological characteristics of TDP-43 accumulation in the cytoplasm in the brain of patients
.
Based on the significant differences between large animals and mice in simulating important pathological changes in neurodegenerative diseases, Li Xiaojiang's team expressed mutant TDP-43 (M337V) in primates and mice substantia nigra in 2019, and found that TDP-43 Monkeys show pathological features similar to the accumulation of cytoplasmic TDP-43 in patients, which is distinct from the accumulation of TDP-43 in the nucleus observed in mouse models [5], which is only specifically expressed in higher animals such as humans and monkeys The hydrolase caspase-4 cleaves TDP-43, so that the TDP-43 fragment product lacking the nuclear localization signal is transferred to the cytoplasm [5]
.
On December 22, 2021, the team of Li Xiaojiang from the Guangdong-Hong Kong-Macao Institute of Central Nervous Regeneration, Jinan University published a study entitled "SQSTM1 mediated clearance of cytoplasmic mutant TARDBP/TDP-43 in the monkey brain" in the journal Autophagy.
research paper
.
By comparing the TDP-43 mouse model, this study found that the SQSTM1 gene in non-human primates is specifically regulated by TDP-43 and its role in clearing cytoplasmic aggregates, once again demonstrating the use of non-human primates.
Importance of animal-like models to study neurodegenerative diseases
.
Researcher Yin Peng of Jinan University is the first author and co-corresponding author, and Professor Li Xiaojiang is the corresponding author of the article
.
In this paper, the authors firstly used viral vector-mediated expression of mutant TDP-43 (M337V) in cynomolgus monkey and mouse model cortical tissues.
Using fluorescent staining, it was found that TDP-43 was expressed as cytoplasmic aggregates in the monkey model.
form, and co-localized signal with SQSTM1 protein can be seen, which is similar to the pathological characteristics of diseases such as ALS and FTLD (Fig.
1A)
.
In addition, TDP-43 in the cytoplasm can specifically promote the instability of primate SQSTM1 (p62) mRNA (Fig.
1B), resulting in decreased SQSTM1 protein expression and impaired autophagic clearance (Fig.
1C), but this phenomenon did not occur in the mouse model
.
Figure 1 In the mutant TDP-43 primate monkey model, but not the mouse model, the cytoplasmic TDP-43 product can promote the instability of SQSTM1 mRNA, resulting in abnormal autophagy function
.
(Source: Yin P, et al.
, Autophagy, 2021) The 3' untranslated region (3' UTR) of mRNA is closely related to post-transcriptional gene expression and is important for biological processes such as mRNA stability and subcellular localization regulation [6,7]
.
By comparing the sequences of the 3'UTR region of SQSTM1 mRNA in humans, cynomolgus monkeys and mice, the authors found that in the 3'UTR region of primates (human and monkey), SQSTM1 mRNA has a longer (TG)n repeat sequence , while in mice, this repeat is only four (TG) repeats (Fig.
2A)
.
Therefore, the authors firstly used RNA immunoprecipitation (Fig.
2B, C) in parallel with RIP-Seq sequencing technology, and found that the expression of TDP-43 cytoplasmic fragment can specifically bind to the 3'UTR region of human SQSTM1 mRNA (Fig.
2D, E ), thereby promoting the degradation of primate SQSTM1 mRNA
.
However, in mice, the 3'UTR region of SQSTM1 lacks longer (TG)n repeats and is not bound by TDP-43, so there is no change in the expression level of SQSTM1
.
Figure 2 Longer (TG)n repeats in the 3'UTR region of primate SQSTM1 bind TDP-43, while short (TG)n repeats in mice do not
.
(Source: Yin P, et al.
, Autophagy, 2021) Next, the authors verified the clearance of TDP-43 aggregates by SQSTM1-mediated abnormal autophagy function
.
It was found that correcting the expression level of SQSTM1, as well as activating the autophagy-regulated pathway, both promoted the clearance of fragmented TDP-43 cytoplasmic aggregates (Fig.
3A,B)
.
Moreover, when SQSTM1 mediated by viral vector is expressed in the mutant TDP-43 model monkey brain, it can restore the autophagic clearance function and promote the reduction of TDP-43 fragmented and aggregated products, thus explaining the function in ALS/FTLD and other disease processes.
The essential role of sexual SQSTM1 in clearing misfolded proteins (Fig.
3C,D)
.
Figure 3 Primate-specific caspase-4 cleaves TDP-43, causing it to accumulate in the cytoplasm and cause cytotoxicity; SQSTM1 promotes the clearance of TDP-43 aggregates
.
(Source: Yin P, et al.
, Autophagy, 2021) The conclusion and discussion, inspiration and prospect of the article are combined with the author's previous report that the hydrolase caspase-4, which is specifically expressed in higher animals such as humans and monkeys, can cleave TDP-43 The TDP-43 fragment product lacking the nuclear localization signal is transferred to the cytoplasm [5]
.
This finding once again proves that the mechanism of ALS pathology is different between non-human primate models and mouse models.
The use of non-human primate models can better study the accumulation and neurotoxicity of TDP-43 in the cytoplasm ( Figure 3E)
.
In recent years, Li Xiaojiang's team found that pigs [8, 9] and monkey models [10, 11] can better simulate the typical pathological changes of neurodegenerative diseases, and some pathogenic related proteins or gene sequences only exist in large animals
.
The study of the TDP-43 monkey model further confirms the need to use large animal and non-human primate models to more accurately reveal the molecular mechanisms of neurodegenerative diseases and find effective treatments
.
Although the expression of mutant TDP-43 in primate cells can be used to study the pathological mechanism of cytoplasmic aggregates, overexpression of TDP-43 is often cytotoxic and cannot reflect the loss of normal TDP-43 in the nucleus.
Toxicity hypothesis, it is necessary to genetically edit endogenous TDP-43 to produce a mutant protein to better describe the neurotoxicity of mutant TDP-43
.
In addition, with the increasing application of large animal models in basic medicine, especially neuroscience research, the shortage of non-human primate monkey resources and its many limitations in feeding, maintenance and operation, researchers need to learn from monkey models.
The discovery of new mechanisms has led to the development and modification of mouse models to better mimic the pathological phenomena of the disease
.
Link to the original text: https://doi.
org/10.
1080/15548627.
2021.
2013653 Group photo of Li Xiaojiang's laboratory: Researcher Yin Peng (third from left) is the first author and co-corresponding author, Professor Li Xiaojiang (fifth from left) is the corresponding author of the article, and Other major contributors
.
(Photo provided by: Li Xiaojiang Laboratory) Jinan University Guo Xiangyu (third from right), associate researcher Li Bang (first from right), etc.
also participated in the research of this project
.
Researcher Wang Lu from the Imaging Center of the First Affiliated Hospital of Jinan University has made important contributions to monkey imaging observations
.
Professor Li Shihua from Jinan University (sixth from left) is also the co-corresponding author of the article
.
This study was funded by the Guangdong Provincial Department of Science and Technology, the National Key R&D Program of the Ministry of Science and Technology, the National Natural Science Foundation of China, and the Guangdong Provincial Key Laboratory Platform for Non-Human Primate Model Research
.
Selected Previous Articles【1】Nat Neurosci︱Cao Peng’s lab discovered the important function of pain perception in the struggle for survival among species【2】Neurosci Bull︱Tongli’s research group revealed that dopaminergic neurons in the VTA-PrL neural pathway are in the rat Sevoflurane plays a wake-promoting effect under general anesthesia 【3】Nat Aging︱New discovery in Alzheimer's disease: a regulatory mechanism of bone marrow-derived macrophages independent of TREM2 pathway 【4】Sci Transl Med︱monoaminergic New evidence of delayed onset of antidepressant drugs: hippocampal cAMP modulates HCN channel function and then affects mouse behavior and memory [5] Nat Methods︱Peng Hanchuan's research group developed cross-modal brain registration technology for brain atlas construction and single-cell accuracy full scale Brain mapping research provides important support [6] Nat Commun︱ astrocytes inhibit the infiltration of peripheral macrophages in non-human primate cerebral ischemia injury [7] Cereb Cortex | Acquired multimodal neuroimaging features【8】Neurosci Bull︱Li Yunqing’s group revealed that neuroplastic changes in the anterior cingulate correlate with hyperalgesia and anxiety in chronic pancreatitis【9】Neuron︱Cao Peng’s laboratory found repetitive stereotyped behaviors The closed-loop neural mechanism of [10] EMBO Rep｜Kang Jiuhong's research group discovered a new mechanism of lncRNA SOX1-OT regulating human ESC neurogenesis Recommended for high-quality scientific research training courses [1] Common experimental paradigm for cognitive control and executive function [2] Single cell Sequencing and Spatial Transcriptomics Data Analysis Symposium Book Donation Event [1] Book Donation︱ Oxford Science Series "Brain" - Insomnia, Anxiety, Do You Really Know Your Brain? References (swipe up and down to view) [1] Rethinking ALS: the FUS about TDP-43.
Cell 136:1001–1004.
[2] TAR DNA-binding protein 43 in neurodegenerative disease.
Nat Rev Neurol 6:211–220.
[ 3] TDP-43 in familial and sporadic frontotem -poral lobar degeneration with ubiquitin inclusions.
Am J Pathol 171:
