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Editor | xi Type C Niemann-Pick disease (NPC) is a neurodegenerative disease associated with abnormal lysosomal lipid storage.
95% of NPC patients are caused by mutations in the lysosomal membrane protein NPC1 gene.
Lysosomes are the main organelles that degrade and clean up harmful garbage in cells, and are an important part of maintaining cell homeostasis.
NPC1 gene defects can cause lipid transport barriers in cells, leading to the deposition of large amounts of free cholesterol in lysosomes and affecting the formation of autophagic lysosomes.
The main early pathological changes of NPC in the nervous system are axon swelling and neuronal degeneration and death caused by lysosomal function defects.
However, the mechanism of its disease in the nervous system is still unclear.
On April 19, 2021, the National Institutes of Health (NIH) Sheng Zuhang team published in Developmental Cell the research results titled Lipid-mediated motor-adaptor sequestration impairs axonal lysosome delivery leading to autophagic stress and dystrophy in Niemann-Pick type C .
This study found a new pathological mechanism of NPC in the nervous system: excessive accumulation of cholesterol on the surface of the lysosome membrane caused abnormal non-functional recruitment of the transport motor protein Kinesin-1 and mediator protein Arl8, thereby reducing the lysosome from the cell body to the axis The transport efficiency of the distal end of the axon causes the loss of autophagy clearance in the axon and leads to the degeneration of the neuron axon.
The four main findings of the study include: 1.
Transmission electron microscopy revealed a large number of autophagic organelles in the axons of the dorsal root and cortex of NPC1 knockout (Npc1-/-) mice.At the same time, in vitro cultured neurons taken from adult mice further confirmed that a large number of autophagosomes were abnormally accumulated in axons.
2.
By labeling the active lysosomal proteases GCase, Cathepsin D and membrane protein Lamp1, the study found that the density of mature lysosomes in the axons of Npc1-/- mice was significantly reduced, but the total amount of lysosomes in the cells increased.
Live cell imaging results showed that in Npc1-/- mice, the forward transport of lysosomes from the cell body to the distal axon was blocked.
3.
In order to explore the mechanism of transport obstruction, Sheng Zuhang's team used STED ultra-high-resolution imaging technology to find that a large amount of cholesterol on the surface of the lysosomal membrane in the Npc1-/- mouse neuron cell accumulated and abnormally recruited motor kinesin-1 And mediating molecule (adaptor) small GTPases Arl8 on the surface of lysosome membrane.
As a result, Kinesin-1 and Arl8 cannot effectively transfer and transport lysosomes to the distal end of axons, thereby preventing lysosomes from performing the function of removing garbage and waste in axons.
4.
The study further found that the application of 2-hydroxypropyl-b-cyclodextrin (HPCD), a cholesterol-lowering chemical agent approved by the FDA, can significantly reduce the cholesterol level on the surface of the lysosome membrane of Npc1-/- mice, thereby inhibiting kinesin-1 and Arl8 Abnormal accumulation restores axoplasmic lysosomal transport and autophagy clearance in axons, thereby repairing neuronal apoptosis.
This result provides a biological basis for the application of cholesterol-lowering drugs HPCD in early treatment.
In conclusion, this study reveals for the first time that the accumulation of cholesterol on the lysosomal membrane leads to an important mechanism of axoplasmic transport disorder and neuronal axon degeneration and death.
The accumulation of lipids on the lysosome surface leads to abnormal and non-functional enrichment of lysosomal axoplasmic transport dynein and mediator molecules on the lysosomal surface, which damages the lysosomal axon transport mechanism, which in turn leads to axon degeneration and nerves Apoptosis.
This study not only reveals the new pathogenic mechanism of NPC in the nervous system, but also provides new ideas and new targets for the early treatment of NPC.
Sheng Zuhang is the corresponding author of the study.
The first author Joseph Roney is a PhD student in the NIH-Cambridge-Oxford joint program, under the tutelage of Sheng Zuhang and Oxford Frances Platt.
The second author, Dr.
Li Sunan, completed the STED ultra-high resolution imaging experiment, which is a mechanism study.
Made an important contribution.
The postdoc of the Sheng team including Tamar Farfel-Becker, Huang Ning, Sun Tao, Xie Yuxiang, Cheng Xiutang, and Mei-Yao Lin also participated in this research and made contributions.
In recent years, Sheng Zuhang’s team has systematically studied neuronal lysosomal autophagosome transport and nervous system function and homeostasis regulation (Cai et al.
, Neuron 2010; Cai et al.
, Current Biology, 2012; Cheng et al.
, JCB 2015 ; Di Giovanni and Sheng, EMBO J 2015; Xie et al.
, Neuron 2015; Cheng et al.
, JCB 2018; Farfel-Becker et al.
, Cell Reports 2019), a number of previously published works are research on the mechanism of this disease A solid foundation was laid. It is also part of their system work.
Original link: https://doi.
org/10.
1016/j.
devcel.
2021.
03.
032 Platemaker: Eleven References 1.
Cai, Q.
, L.
Lu, J.
-H.
Tian, Y.
-B.
Zhu, H.
Qiao, and Z.
-H.
Sheng (2010).
Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons.
Neuron 68, 73-86.
2.
Cai, Q.
, HM Zakaria, A.
Simone, and Z.
-H.
Sheng (2012).
Spatial Parkin Translocation and Degradation of Depolarized Mitochondria via Mitophagy in Live Cortical Neurons.
Current Biology 22, 545-552.
3.
Cheng, X.
-T .
, B.
Zhou, M.
-Y.
Lin, Q.
Cai, and Z.
-H.
Sheng (2015).
Axonal autophagosomes acquire dynein motors for retrograde transport through fusion with late endosomes.
Journal of Cell Biology 209, 377- 386.
4.
Di Giovanni, J.
, and Z.
-H.
Sheng (2015).
Regulation of synaptic activity by snapin-mediated endolysosomal transport and sorting.
EMBO Journal 34, 2059-2077.
5.
Xie* Y,Zhou B* (equal contributions), Lin MY, Wang S, Foust KD, and Sheng ZH.
(2015).
Endolysosome deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS-linked mice.
Neuron 87, 355-370.
6.
Cheng XT , Xie Y, Zhou B, Huang N, Farfel-Becker T, and Sheng ZH (2018).
Characterization of LAMP1-labeled non-degradative lysosomal and endocytic compartments in nervous systems.
Journal of Cell Biology 217, 3127-3139.
7.
Farfel- Becker T, Roney JC, Cheng XT, Li S, Cuddy SR, and Sheng ZH.
(2019).
Neuronal soma-derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity.
Cell Reports 28, 51-64.
Reprinted Note [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated.
Endolysosome deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS-linked mice.
Neuron 87, 355-370.
6.
Cheng XT, Xie Y, Zhou B, Huang N, Farfel-Becker T, and Sheng ZH (2018).
Characterization of LAMP1 -labeled non-degradative lysosomal and endocytic compartments in nervous systems.
Journal of Cell Biology 217, 3127-3139.
7.
Farfel-Becker T, Roney JC, Cheng XT, Li S, Cuddy SR, and Sheng ZH.
(2019).
Neuronal soma -derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity.
Cell Reports 28, 51-64.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting without permission is prohibited, the author Have all statutory rights and offenders must be investigated.
Endolysosome deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS-linked mice.
Neuron 87, 355-370.
6.
Cheng XT, Xie Y, Zhou B, Huang N, Farfel-Becker T, and Sheng ZH (2018).
Characterization of LAMP1 -labeled non-degradative lysosomal and endocytic compartments in nervous systems.
Journal of Cell Biology 217, 3127-3139.
7.
Farfel-Becker T, Roney JC, Cheng XT, Li S, Cuddy SR, and Sheng ZH.
(2019).
Neuronal soma -derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity.
Cell Reports 28, 51-64.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting without permission is prohibited, the author Have all statutory rights and offenders must be investigated.
Characterization of LAMP1-labeled non-degradative lysosomal and endocytic compartments in nervous systems.
Journal of Cell Biology 217, 3127-3139.
7.
Farfel-Becker T, Roney JC, Cheng XT, Li S, Cuddy SR, and Sheng ZH.
(2019) .
Neuronal soma-derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity.
Cell Reports 28, 51-64.
Reprint instructions [Non-original articles] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, and it is prohibited without permission Reprinted, the author has all legal rights, offenders must be investigated.
Characterization of LAMP1-labeled non-degradative lysosomal and endocytic compartments in nervous systems.
Journal of Cell Biology 217, 3127-3139.
7.
Farfel-Becker T, Roney JC, Cheng XT, Li S, Cuddy SR, and Sheng ZH.
(2019) .
Neuronal soma-derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity.
Cell Reports 28, 51-64.
Reprint instructions [Non-original articles] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, and it is prohibited without permission Reprinted, the author has all legal rights, offenders must be investigated.
95% of NPC patients are caused by mutations in the lysosomal membrane protein NPC1 gene.
Lysosomes are the main organelles that degrade and clean up harmful garbage in cells, and are an important part of maintaining cell homeostasis.
NPC1 gene defects can cause lipid transport barriers in cells, leading to the deposition of large amounts of free cholesterol in lysosomes and affecting the formation of autophagic lysosomes.
The main early pathological changes of NPC in the nervous system are axon swelling and neuronal degeneration and death caused by lysosomal function defects.
However, the mechanism of its disease in the nervous system is still unclear.
On April 19, 2021, the National Institutes of Health (NIH) Sheng Zuhang team published in Developmental Cell the research results titled Lipid-mediated motor-adaptor sequestration impairs axonal lysosome delivery leading to autophagic stress and dystrophy in Niemann-Pick type C .
This study found a new pathological mechanism of NPC in the nervous system: excessive accumulation of cholesterol on the surface of the lysosome membrane caused abnormal non-functional recruitment of the transport motor protein Kinesin-1 and mediator protein Arl8, thereby reducing the lysosome from the cell body to the axis The transport efficiency of the distal end of the axon causes the loss of autophagy clearance in the axon and leads to the degeneration of the neuron axon.
The four main findings of the study include: 1.
Transmission electron microscopy revealed a large number of autophagic organelles in the axons of the dorsal root and cortex of NPC1 knockout (Npc1-/-) mice.At the same time, in vitro cultured neurons taken from adult mice further confirmed that a large number of autophagosomes were abnormally accumulated in axons.
2.
By labeling the active lysosomal proteases GCase, Cathepsin D and membrane protein Lamp1, the study found that the density of mature lysosomes in the axons of Npc1-/- mice was significantly reduced, but the total amount of lysosomes in the cells increased.
Live cell imaging results showed that in Npc1-/- mice, the forward transport of lysosomes from the cell body to the distal axon was blocked.
3.
In order to explore the mechanism of transport obstruction, Sheng Zuhang's team used STED ultra-high-resolution imaging technology to find that a large amount of cholesterol on the surface of the lysosomal membrane in the Npc1-/- mouse neuron cell accumulated and abnormally recruited motor kinesin-1 And mediating molecule (adaptor) small GTPases Arl8 on the surface of lysosome membrane.
As a result, Kinesin-1 and Arl8 cannot effectively transfer and transport lysosomes to the distal end of axons, thereby preventing lysosomes from performing the function of removing garbage and waste in axons.
4.
The study further found that the application of 2-hydroxypropyl-b-cyclodextrin (HPCD), a cholesterol-lowering chemical agent approved by the FDA, can significantly reduce the cholesterol level on the surface of the lysosome membrane of Npc1-/- mice, thereby inhibiting kinesin-1 and Arl8 Abnormal accumulation restores axoplasmic lysosomal transport and autophagy clearance in axons, thereby repairing neuronal apoptosis.
This result provides a biological basis for the application of cholesterol-lowering drugs HPCD in early treatment.
In conclusion, this study reveals for the first time that the accumulation of cholesterol on the lysosomal membrane leads to an important mechanism of axoplasmic transport disorder and neuronal axon degeneration and death.
The accumulation of lipids on the lysosome surface leads to abnormal and non-functional enrichment of lysosomal axoplasmic transport dynein and mediator molecules on the lysosomal surface, which damages the lysosomal axon transport mechanism, which in turn leads to axon degeneration and nerves Apoptosis.
This study not only reveals the new pathogenic mechanism of NPC in the nervous system, but also provides new ideas and new targets for the early treatment of NPC.
Sheng Zuhang is the corresponding author of the study.
The first author Joseph Roney is a PhD student in the NIH-Cambridge-Oxford joint program, under the tutelage of Sheng Zuhang and Oxford Frances Platt.
The second author, Dr.
Li Sunan, completed the STED ultra-high resolution imaging experiment, which is a mechanism study.
Made an important contribution.
The postdoc of the Sheng team including Tamar Farfel-Becker, Huang Ning, Sun Tao, Xie Yuxiang, Cheng Xiutang, and Mei-Yao Lin also participated in this research and made contributions.
In recent years, Sheng Zuhang’s team has systematically studied neuronal lysosomal autophagosome transport and nervous system function and homeostasis regulation (Cai et al.
, Neuron 2010; Cai et al.
, Current Biology, 2012; Cheng et al.
, JCB 2015 ; Di Giovanni and Sheng, EMBO J 2015; Xie et al.
, Neuron 2015; Cheng et al.
, JCB 2018; Farfel-Becker et al.
, Cell Reports 2019), a number of previously published works are research on the mechanism of this disease A solid foundation was laid. It is also part of their system work.
Original link: https://doi.
org/10.
1016/j.
devcel.
2021.
03.
032 Platemaker: Eleven References 1.
Cai, Q.
, L.
Lu, J.
-H.
Tian, Y.
-B.
Zhu, H.
Qiao, and Z.
-H.
Sheng (2010).
Snapin-regulated late endosomal transport is critical for efficient autophagy-lysosomal function in neurons.
Neuron 68, 73-86.
2.
Cai, Q.
, HM Zakaria, A.
Simone, and Z.
-H.
Sheng (2012).
Spatial Parkin Translocation and Degradation of Depolarized Mitochondria via Mitophagy in Live Cortical Neurons.
Current Biology 22, 545-552.
3.
Cheng, X.
-T .
, B.
Zhou, M.
-Y.
Lin, Q.
Cai, and Z.
-H.
Sheng (2015).
Axonal autophagosomes acquire dynein motors for retrograde transport through fusion with late endosomes.
Journal of Cell Biology 209, 377- 386.
4.
Di Giovanni, J.
, and Z.
-H.
Sheng (2015).
Regulation of synaptic activity by snapin-mediated endolysosomal transport and sorting.
EMBO Journal 34, 2059-2077.
5.
Xie* Y,Zhou B* (equal contributions), Lin MY, Wang S, Foust KD, and Sheng ZH.
(2015).
Endolysosome deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS-linked mice.
Neuron 87, 355-370.
6.
Cheng XT , Xie Y, Zhou B, Huang N, Farfel-Becker T, and Sheng ZH (2018).
Characterization of LAMP1-labeled non-degradative lysosomal and endocytic compartments in nervous systems.
Journal of Cell Biology 217, 3127-3139.
7.
Farfel- Becker T, Roney JC, Cheng XT, Li S, Cuddy SR, and Sheng ZH.
(2019).
Neuronal soma-derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity.
Cell Reports 28, 51-64.
Reprinted Note [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights and offenders must be investigated.
Endolysosome deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS-linked mice.
Neuron 87, 355-370.
6.
Cheng XT, Xie Y, Zhou B, Huang N, Farfel-Becker T, and Sheng ZH (2018).
Characterization of LAMP1 -labeled non-degradative lysosomal and endocytic compartments in nervous systems.
Journal of Cell Biology 217, 3127-3139.
7.
Farfel-Becker T, Roney JC, Cheng XT, Li S, Cuddy SR, and Sheng ZH.
(2019).
Neuronal soma -derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity.
Cell Reports 28, 51-64.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting without permission is prohibited, the author Have all statutory rights and offenders must be investigated.
Endolysosome deficits augment mitochondria pathology in spinal motor neurons of asymptomatic fALS-linked mice.
Neuron 87, 355-370.
6.
Cheng XT, Xie Y, Zhou B, Huang N, Farfel-Becker T, and Sheng ZH (2018).
Characterization of LAMP1 -labeled non-degradative lysosomal and endocytic compartments in nervous systems.
Journal of Cell Biology 217, 3127-3139.
7.
Farfel-Becker T, Roney JC, Cheng XT, Li S, Cuddy SR, and Sheng ZH.
(2019).
Neuronal soma -derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity.
Cell Reports 28, 51-64.
Reprinting instructions [Non-original articles] The copyright of this article belongs to the author of the article.
Personal forwarding and sharing are welcome.
Reprinting without permission is prohibited, the author Have all statutory rights and offenders must be investigated.
Characterization of LAMP1-labeled non-degradative lysosomal and endocytic compartments in nervous systems.
Journal of Cell Biology 217, 3127-3139.
7.
Farfel-Becker T, Roney JC, Cheng XT, Li S, Cuddy SR, and Sheng ZH.
(2019) .
Neuronal soma-derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity.
Cell Reports 28, 51-64.
Reprint instructions [Non-original articles] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, and it is prohibited without permission Reprinted, the author has all legal rights, offenders must be investigated.
Characterization of LAMP1-labeled non-degradative lysosomal and endocytic compartments in nervous systems.
Journal of Cell Biology 217, 3127-3139.
7.
Farfel-Becker T, Roney JC, Cheng XT, Li S, Cuddy SR, and Sheng ZH.
(2019) .
Neuronal soma-derived degradative lysosomes are continuously delivered to distal axons to maintain local degradation capacity.
Cell Reports 28, 51-64.
Reprint instructions [Non-original articles] The copyright of this article belongs to the author of the article, personal forwarding and sharing are welcome, and it is prohibited without permission Reprinted, the author has all legal rights, offenders must be investigated.
