​Journal of Cell Biology Collector's Edition Review Sheng Zuhang's team summarizes the important role of neuronal endosome-lysosomal transport and function in maintaining axon homeostasis

On February 10, 2022, Zuhang Sheng's team from the National Institutes of Health published a special review on Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis in the Journal of Cell Biology
.

This article provides an in-depth discussion of the regulatory mechanisms of endosome-lysosomal axonal transport and distribution in normal neurons, as well as the important role of lysosomal maturation and function in maintaining neuronal survival, and further elucidates the occurrence of both.
The critical role of post-disorder in neurodegenerative diseases and neuropathological changes in Lysosomal Storage Disorders
.

Based on the laboratory's long-term research experience on neuronal lysosomes, this paper systematically introduces the experimental guidelines for labeling functional lysosomes in neurons
.

The first and second authors of this article are Joseph Roney and Xiu-Tang Cheng respectively
.

Lysosomes are a class of organelles that mainly play a role in degradation, containing more than 60 kinds of acid hydrolases, which are used to degrade various biological macromolecules, including proteins, lipids, nucleic acids and carbohydrates; in addition, lysosomes also have More than 200 membrane proteins are responsible for their intracellular acidification, transport of substances inside and outside organelles, fusion and transport between organelles,
etc.

Neurons are structurally highly polar cells, with axonal sections up to several hundred centimeters long compared to their cell bodies (about 20 microns in diameter), which make up most of the neuron's cytoplasm
.

Functional mature lysosomes are involved in the degradation of various components in the endocytosis-autophagy pathway; extracellular substances can enter neurons through the endocytosis pathway, and undergo early endocytosis in the process of retrograde transport from the neuron terminal to the cell body.
The mature lysosome and late endosome gradually form into mature lysosome, and finally degrade
.

Intracellular substances can also be degraded from the early autophagic body, the amphiphilic autophagic body to the final lysosome by fusion with the endosome and lysosome through the autophagic pathway
.

Due to the particularity of the neuron structure, and most mature lysosomes are located in the cell body, the long-distance transport of lysosomes in the neuron axon has become an important part of its synthesis, maturation and normal function, and is essential for the maintenance of neuronal axons.
The homeostasis of the meta is crucial
.

Lysosomal axonal transport disorder and its own degradation function are mutually causal, which directly or indirectly lead to the occurrence and development of most neurodegenerative diseases
.

In the field of neurobiology, researchers often need to comprehensively consider the complementary relationship between lysosomal function and transport
.

This is a feature of neuronal lysosomes that cannot be ignored, different from other non-neuronal cells, yet this feature is often overlooked in research
.

In addition, due to the confusion over the definition of functional lysosomes and the limitation of detection technology, there are differences in the distribution and function of lysosomes in neurons, which hinders the in-depth study of diseases related to lysosomal defects
.

The main axonal transport mode of normal neuronal endosome-lysosome and its regulatory mechanism The transport motor protein dynein-dynactin complex, and the co-ordination of multiple linker proteins
.

This paper first summarizes the relevant mechanisms of the classic endosome-lysosome axonal transport and its effect on autophagosome mature degradation, and further discusses the latest research results, including 1) the forward axon of mature lysosomes Transport and function; 2) Endosome/lysosome as a platform for RNA particle axonal transport; 3) Endoplasmic reticulum regulation of endosome-lysosome axonal transport,
etc.

In addition, the transport and distribution of lysosomes in various compartments of neurons are simultaneously regulated by the neuron's own metabolic state and synaptic activity
.

This paper discusses the latest regulatory mechanisms in detail from the functional requirements of neurons as a whole, such as changes in synaptic activity, supply and demand of nutrients; and the state of lysosomes themselves, such as acidity, calcium release,
etc.

These mechanisms play an important role in the normal functioning of neurons and the maintenance of homeostasis, including their synaptic plasticity, local energy demands, and possible stress states
.

The relationship between lysosomal function and axonal transport disorders and the development of neurodegenerative diseases Neuronal axon degeneration is a hallmark feature of many neurodegenerative diseases, and endosome-lysosomes are often found in degenerated axons - Abnormal accumulation of organelles involved in the autophagic pathway, reflecting maturation defects and/or clearance dysfunction in these organelles
.

Because the organelles included in the endosome-lysosome-autosome pathway are all over the neuron axons, any obstacle in the long-distance transport process can lead to the abnormal accumulation of these organelles in the axons, which can lead to the development of diseases.
important factor
.

This paper systematically discusses the major neurodegenerative diseases (such as Alzheimer's disease, Parkinson's disease, myo- The latest research results of the pathological development mechanism of atrophic lateral sclerosis) and lysosomal storage diseases (such as type C Niemann-Pick disease)
.

These studies deepened our understanding of the important role of neuronal lysosomes in neurodegenerative diseases and provided a new theoretical basis for the development of possible therapeutic strategies in the future
.

Guidelines for the detection of mature lysosomes in neurons (Guidelines) With the long-distance retrograde transport of axons, various intermediate organelles of endocytic and autophagic pathways in neurons are transmitted and transformed through different components, and finally form a function of degradation mature lysosomes
.

These heterogeneous intermediates have different morphologies, membrane surface components, types of hydrolases, acidity, and degradability, and this heterogeneity represents various maturation stages of the endocytic-autotrophic pathway
.

Generally, mature lysosomes have the following main criteria: 1.
It is an organelle with a single-layer membrane structure, which contains a hydrolase with a degrading function, and is matched with an acidic environment (pH 4.
5-5); 2.
The membrane contains Highly glycosylated lysosome-associated membrane protein 1/2 (LAMP1/2); 3.
It contains degradation products; 4.
It does not contain endosomal-specific marker proteins, such as mannose-6-phosphate receptors ( M6PR),
etc.

However, because related studies in the field often use LAMP1/2 or LysoTracker, etc.
(protein components distributed in most endocytic-autophilic systems) to label lysosomes, many labeled organelles have not reached mature lysis.
Enzyme standard, no degradation function
.

Therefore, this paper highlights some guidelines for labeling lysosomes, including the combined use of various probes based on hydrolase activity; the use of Bouin's fixative instead of 4% PFA to detect lysosomal hydrolase staining methods,
etc.

These improved technical means based on living cells or fixed cells can more sensitively detect lysosomes in various compartments of neurons, so as to reflect their distribution and function more realistically, and promote the neuroscience field of mature lysosomes in neurons.
The study of axonal transport and its function in physiopathological conditions
.

In conclusion, efficient endosomal-lysosome-autophagosome bidirectional axonal transport is not only indispensable for the function of lysosome itself, but also crucial for axonal homeostasis
.

The disturbance of axonal transport and the loss of axonal homeostasis are involved in the occurrence and development of various neurodegenerative diseases
.

This review summarizes the latest research progress in the field and proposes detection standards for neuronal lysosomes, which lays the foundation for in-depth research on the mechanism of related diseases
.

At the end of the article, the author proposes many research directions to be explored
.

The laboratory is currently recruiting postdoctoral fellows.
For specific research content and application methods, please visit https://research.
ninds.
nih.
gov/sheng-lab/postdoctoral-fellowship-opening Attached to the research results and reviews reported by the Sheng Zuhang team in BioArt in the past year: 1.
(2020) Cell Metabolism | The joint research results of Xu Xiaoming/Sheng Zuhang team improve energy supply and help recovery from spinal cord injury 2.
(2020) Nat Metabolism | Sheng Zuhang team reveals a new mechanism for mitochondria to participate in presynaptic energy metabolism regulation 3.
(2021) Dev Cell | Sheng Zuhang's team reveals the neurodegenerative pathogenic mechanism of nerve cell lysosomal transport disorder in type C Niemann-Pick disease 4.
(2021) Current Biology | Sheng Zuhang's team reveals that neuronal axonal injury response signals regulate energy metabolism and promote New mechanisms of survival and regeneration after injury ) Nature Reviews Neuroscience | Sheng Zuhang's team focused on the important role of presynaptic local energy metabolism in nerve conduction Original link: https://rupress.
org/jcb/article/221/3/e202111077/213000/Neuronal-endolysosomal-transport- and-lysosomal Publisher: 11 Reprint Notice [Non-original article] The copyright of this article belongs to the author of the article.
Personal reposting and sharing are welcome.
Reprinting is prohibited without permission.
The author has all legal rights, and offenders must be prosecuted.

.