Neuronal Soma-Derived Degradative Lysosomes Are Continuously Delivered to Distal Axons to Maintain Local Degradation Capacity

Abstract

SUMMARY Neurons face the challenge of maintaining cellular homeostasis through lysosomal degradation. While enzymatically active degradative lysosomes are enriched in the soma, their axonal trafficking and positioning and impact on axonal physiology remain elusive. Here, we characterized axon-targeted delivery of degradative lysosomes by applying fluorescent probes that selectively label active forms of lysosomal cathepsins D, B, L, and GCase. By time-lapse imaging of cortical neurons in microfluidic devices and standard dishes, we reveal that soma-derived degradative lysosomes rapidly influx into distal axons and target to autophagosomes and Parkinson disease-related α-synuclein cargos for local degradation. Impairing lysosome axonal delivery induces an aberrant accumulation of autophagosomes and α-synuclein cargos in distal axons. Our study demonstrates that the axon is an active compartment for local degradation and reveals fundamental aspects of axonal lysosomal delivery and maintenance. Our work establishes a foundation for investigations into axonal lysosome trafficking and functionality in neurodegenerative diseases.

Synaptic Vesicle Precursors and Lysosomes Are Transported by Different Mechanisms in the Axon of Mammalian Neurons

“…LAMP1 is concentrated mainly in lysosomes, although significant amounts are also found in early and late endosomes ( Fermie et al, 2018 ), a reflection of its transport to lysosomes via the endocytic pathway ( Lippincott-Schwartz and Fambrough, 1987 ; Janvier and Bonifacino, 2005 ; Chen et al, 2017 ). In axons, LAMP1-positive vesicles are heterogeneous, with some having an acidic luminal pH and acid hydrolases (i.e., conventional lysosomes), while others are neutral and lack acid hydrolases ( Lee et al, 2011 ; Gowrishankar et al, 2015 ; Farías et al, 2017 ; Cheng et al, 2018 ; Vukoja et al, 2018 ; Farfel-Becker et al, 2019 ). This heterogeneity notwithstanding, for simplicity, herein we refer to all LAMP1-positive vesicles as lysosomes.…”

“…Lysosomes are membrane-bound, acidic organelles that are primarily involved in intracellular degradation of biomacromolecules but also participate in various non-degradative processes such as nutrient and growth factor signaling and plasma membrane repair ( Ballabio and Bonifacino, 2020 ). Axonal lysosomes are particularly heterogeneous with regard to their degradative capacity and acidity ( Lee et al, 2011 ; Gowrishankar et al, 2015 ; Farías et al, 2017 ; Cheng et al, 2018 ; Farfel-Becker et al, 2019 ), a property that may reflect the existence of populations of lysosomes with distinct functions or maturational states ( Ferguson, 2019 ). In mammals, anterograde lysosome transport depends on coupling to several members of the kinesin family, especially the kinesin-1 proteins KIF5A, KIF5B, and KIF5C, and kinesin-3 proteins KIF1A and KIF1Bβ ( Nakata and Hirokawa, 1995 ; Tanaka et al, 1998 ; Matsushita et al, 2004 ; Guardia et al, 2016 ; Farías et al, 2017 ).…”

Degradation and Transmission of Tau by Autophagic-Endolysosomal Networks and Potential Therapeutic Targets for Tauopathy

“…This retrograde transport of autophagosomes along the microtubule is dynein-and activity-dependent in granule cells (Katsumata et al, 2010). It was recently reported that soma-derived degradative lysosomes are anterogradely transported to the distal axon to fuse with autophagosomes to form autolysosomes, which are later retrogradely transported to the soma for degradation in mouse cortical neurons at DIV 14 (Farfel-Becker et al, 2019). In disease neurons, impaired axonal delivery of lysosome causes autophagic stress.…”

“…Indeed, accumulation of lysosomes, lysosomal hydrolases, autophagosome, autophagic vacuoles, multi-vesicular bodies (MVBs), autolysosomes, and defect in lysosomal membrane integrity in the brain has been reported in AD, CBD, and PSP patients (Nixon et al, 2005;Nixon, 2013;Piras et al, 2016;Menzies et al, 2017). Defects in the retrograde transportation of autophagosomes from axon to soma and antegrade transportation of degradative lysosomes to distal axons were also demonstrated (Farfel-Becker et al, 2019). On the other hand, fragmented tau can impair CMA and lysosomal dysfunction and lead to tau oligomerization and aggregation (Wang et al, 2009).…”

Endosomal Sorting Drives the Formation of Mutant Prion Endoggresomes

“…To regulate function, polarized neurons rely largely on active microtubule-based transport to localize components to distal axonal domains via kinesin-mediated anterograde movement 3 . As the axon has important but limited lysosomal degradative capacity 4 , long-distance dynein-dependent retrograde transport of axonal cargoes back to the lysosome-enriched soma is critical for their efficient degradation 5, 6 . Neuronal homeostasis also depends on an interconverting endo-lysosomal system that spreads over long axonal distances, to regulate sorting, signaling, and metabolic functions 7 .…”