Lysosome and Endosome in Neurons

The Lysosome-Endosome Systems

The lysosome and endosomal system are part of the cell’s central vacuolar system through which secretory and membrane proteins are synthesized, modified, delivered to appropriate cellular compartments, and eventually degraded. This system, which is exceptionally well developed in neurons, consists of five significant compartments, including early endosomes, late endosomes, autophagic vacuoles, lysosomes, and residual bodies. The catabolic activity of this system allows cells to clear unwanted materials and generate nutrients in times of stress support diverse cellular functions.

Fig.1 The neuronal lysosome-endosome system. (Nixon, 2001)

Lysosomes allow the degradation of macromolecules derived from the extracellular space through endocytosis or phagocytosis and from the cytoplasm through autophagy. Also, a network of lysosomal proteins and other cellular constituents such as endosomes contribute to the delivery of lysosomal proteins and substrates. To this end, endosomes could act as an intermediate between secretory pathways and support protein subsequent delivery to lysosomes. Acidification of the late endosome is accompanied by vesicle trafficking, protein sorting, and targeted degradation of some sorted cargo. Thus, lysosomes do not function in isolation from other organelles but require continuous delivery of both cargos and hydrolases from the endocytic and autophagic pathways.

Table 1. Major compartments of the lysosome-endosome system. (Nixon, 1995)

Roles of Lysosome and Endosome in Neurons

The lysosome-endosome system has potential roles in modifying functions of specific proteins, acquiring nutrients essential for growth and repair, influencing the output of secretory products, and helping neurons to modulate trophic signals.

• Lysosome in Neurons

The lysosome serves critical roles in a wide range of cellular functions, including cell clearance, signaling, metabolism, and homeostasis. Moreover, lysosomes could also serve as a signaling platform that integrates nutrient and metabolic cues to control signaling pathways. It has critical roles in some of the most vital processes like repairing the plasma membrane and energy metabolism. Of particular interest is that lysosomes are dynamically distributed throughout neuronal sub-compartments and perform a broad range of hydrolytic and signaling functions relevant to neuronal physiology and pathophysiology.

• The Endocytic Pathway

Considering the importance of endocytosis to neurons is instructive in understanding how endosome dysfunction may contribute to neurodegeneration in many neurodegenerative diseases. In neurons, the endocytic pathway enables modifying or degradation of molecules from the cell surface in intracellular compartments through a series of vesicular budding and fusion events. One of the functions of endocytosis unique to neurons is synaptic transmission. After neurotransmitter release, synaptic vesicles must be reformed by a rapid endocytic process to maintain synaptic vesicle number during the period of synaptic activation. In addition, neurons also rely heavily on endocytosis to mediate communication with peripheral tissues necessary for survival. Therefore, the endocytic pathway plays a critical role in internalizing extracellular nutrients, degrading receptors and other integral membrane proteins after neurotransmitter release, and direct information to intracellular biosynthetic pathways.

Fig.2 The lysosome-endosome system and AD. (Hu, 2015)

Relationships Between Lysosome-Endosome System and Neurodegenerative Diseases

Neurodegenerative diseases are characterized by progressive dysfunction and the death of cells that frequently affect specific neural systems, including Alzheimer’s disease (AD) and Parkinson’s disease (PD). The lysosome-endosome system is a central player in many neurodegenerative diseases and shows potential pathogenesis and viable therapeutic strategies. In AD, a progressive neurodegenerative disorder, robust activation of the neuronal lysosomal system and cellular pathways converging on the lysosome, such as the autophagic and endocytic pathways, are this disease’s prominent neuropathological features. Abnormal protein degradation and deposition induced by lysosomal dysfunction may be the primary contributor to age-related neurodegeneration. New evidence shows disturbances of the neuronal endocytic pathway, one of the earliest known intracellular changes in AD. It provides insight into how amyloidogenesis might be promoted in sporadic AD, the most prevalent and most diminutive well-understood form of the disease.

Table 2. The pathogenesis and lysosomes in neurodegenerative diseases. (Zhang, 2009)

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References

1. Nixon, R. A.; et al. The neuronal endosomal-lysosomal system in Alzheimer's disease. Journal of Alzheimer’s Disease. 2001, 3(1), 97-107.
2. Nixon, R. A.; Cataldo, A. M. The endosomal-lysosomal system of neurons: new roles. Trends in neurosciences. 1995, 18(11), 489-496.
3. Hu, Y. B.; et al. The endosomal-lysosomal system: from acidification and cargo sorting to neurodegeneration. Translational neurodegeneration. 2015, 4(1), 1-10.
4. Zhang, L.; et al. The lysosome and neurodegenerative diseases. Acta biochimica et biophysica Sinica. 2009, 41(6), 437-445.