Neuronal lysosomes

Abstract

Lysosomes support diverse cellular functions by acting as sites of macromolecule degradation and nutrient recycling. The degradative abilities of lysosomes are conferred by a lumen that is characterized by an acidic pH and which contains numerous hydrolases that support the breakdown of major cellular macromolecules to yield cellular building blocks (amino acids, nucleic acids, sugars, lipids and metals) that are transported into the cytoplasm for their re-use. In addition to these important hydrolytic and recycling functions, lysosomes also serve as a signaling platform that integrates nutrient and metabolic cues to control signaling via the mTORC1 pathway. Due to their extreme longevity, polarity, demands of neurotransmission and metabolic activity, neurons are particularly sensitive to perturbations in lysosome function. The dependence of neurons on optimal lysosome function is highlighted by insights from human genetics that link lysosome dysfunction to a wide range of both rare and common neurological diseases. How then is lysosome function adapted to the unique demands of neurons? This review will focus on the roles played by lysosomes in distinct neuronal sub-compartments, the regulation of neuronal lysosome sub-cellular localization and the implications of such neuronal lysosome regulation for both physiology and disease.

Keywords: Alzheimer's disease; Autophagosome; Axon; Dendrite; Endosome; Hereditary spastic paraplegia; Lysosome; mTORC1.

Figure 1

Schematic representation of the dependence of lysosomes on membrane traffic from the secretory pathway (ER and Golgi) to endosomes for the delivery of proteins supporting lysosome biogenesis and maintenance. Meanwhile, the endocytic and autophagy pathways both deliver substrates for lysosomes to degrade. Although all of these organelles can be found in close proximity in neuronal cell bodies, the Golgi is not found in axons. Meanwhile autophagosomes form robustly in distal parts of neurons that can be separated from the cell body by more than a meter in the longest human neurons. This raises challenges for the ability of lysosomes to receive newly synthesized enzymes from the secretory pathway in order to mediate degradative functions at the most distal sites within neurons.

Figure 2

Confocal image of lysosomes (LAMP1 signal, green) in mouse cortical neurons in culture along with MAP2B staining (red) which labels microtubules of neuronal dendrites. The asterisks indicate the position of non-neuronal lysosome signals arising from underlying glial cells. Although LAMP1 staining is commonly used to define lysosome distribution, due to the close relationship between lysosomes and other organelles of the secretory and endocytic pathways (Figure 1), the use of antibodies against multiple lysosomal proteins, including luminal hydrolases, is advisable for the definitive lysosome identification (Scale bar = 10 μm).