ER – lysosome contacts at a pre-axonal region regulate axonal lysosome availability

Abstract

Neuronal function relies on careful coordination of organelle organization and transport. Kinesin-1 mediates transport of the endoplasmic reticulum (ER) and lysosomes into the axon and it is increasingly recognized that contacts between the ER and lysosomes influence organelle organization. However, it is unclear how organelle organization, inter-organelle communication and transport are linked and how this contributes to local organelle availability in neurons. Here, we show that somatic ER tubules are required for proper lysosome transport into the axon. Somatic ER tubule disruption causes accumulation of enlarged and less motile lysosomes at the soma. ER tubules regulate lysosome size and axonal translocation by promoting lysosome homo-fission. ER tubule – lysosome contacts often occur at a somatic pre-axonal region, where the kinesin-1-binding ER-protein P180 binds microtubules to promote kinesin-1-powered lysosome fission and subsequent axonal translocation. We propose that ER tubule – lysosome contacts at a pre-axonal region finely orchestrate axonal lysosome availability for proper neuronal function.

Current methods to analyze lysosome morphology, positioning, motility and function

“…131 BiFC has been widely used to study MCS, including lysosome contacts with the ER, 135 but requires expression of constructs that may themselves affect the MCS stability. An alternative, but similar approach to BiFC, is dimerization-dependent fluorescent proteins (ddFP) that require binding of two weakly fluorescent monomers, which can be targeted to different organelles, for example lysosomes and ER, 136 to form a much brighter fluorescent dimer on protein-protein interaction at MCS. 133,137 The reversible interaction is unlikely to affect MCS stability but background signal from each weakly fluorescent monomer needs to be considered.…”

Neuronal endolysosomal transport and lysosomal functionality in maintaining axonostasis

“…3 C ; Matsuzaki et al, 2011 ; Palomo-Guerrero et al, 2019 ; Raiborg et al, 2015 ). In addition, contact sites between ER tubules and endolysosomes at pre-axonal regions can drive lysosome transport into axons ( Ozkan et al, 2021 ). These ER–lysosome contacts regulate lysosome size through kinesin-1–mediated fission, resulting in the subsequent delivery of newly reformed lysosomes to distal axons.…”

Inter-organellar Communication in Parkinson's and Alzheimer's Disease: Looking Beyond Endoplasmic Reticulum-Mitochondria Contact Sites

“…Furthermore, in mammals, MCSs may exert neuronal-specific functions, underlining a specific involvement in NDs. For example, ER tubules in contact with Lys promote lysosomal fission in the pre-axonal region, and subsequent kinesin-1-dependent Lys translocation into the axon (Özkan et al, 2021 ). Vice versa , VAPA-mediated ER-Lys contacts are necessary for ER elongation and network formation, whereby Lys reposition ER tubules to adapt to metabolic changes and to promote axon outgrowth (Lu et al, 2020 ).…”