The Amyloid Precursor-like Protein APL-1 Regulates Axon Regeneration

Abstract

Members of the Amyloid Precursor Protein (APP) family have important functions during neuronal development. However, their physiological functions in the mature nervous system are not fully understood. Here we use the C. elegans GABAergic motor neurons to study the postdevelopmental function of the APP-like protein APL-1 in vivo. We find that apl-1 has minimum roles in the maintenance of gross neuron morphology and function. However, we show that apl-1 is an inhibitor of axon regeneration, acting on mature neurons to limit regrowth in response to injury. The small GTPase Rab6/RAB-6.2 also inhibits regeneration, and does so in part by maintaining protein levels of APL-1. To inhibit regeneration, APL-1 functions via the E2 domain of its ectodomain; the cytoplasmic tail, transmembrane anchoring, and the E1 domain are not required for this function. Our data defines a novel role for APL-1 in modulating the neuronal response to injury.

rab-27acts in an intestinal secretory pathway to inhibit axon regeneration inC. elegans

“…C. elegans provides an excellent system to probe the "rabome" for novel pathways affecting axon regeneration. In C. elegans, rab-6.2 was previously shown to affect regeneration (Zeng et al 2018), as was rab-27 function in neurons (Sekine et al 2018). This work probed the function of RAB-27 outside the nervous system, revealing an unexpected role for DCV fusion in the intestine in regulation of axon regeneration.…”

“…5A). In addition to rab-27 and the previously identified rab-6.2 (Zeng et al 2018), loss of rab-18 significantly decreases regeneration success, while loss of glo-1 leads to a modest increase in regeneration. Unlike other high-regenerating Rab mutants, glo-1 mutants specifically show an increase in full regeneration after 24 hours of recovery, though not an increase in the likelihood of regeneration initiation during that period (Fig.…”

rab-27 acts in an intestinal pathway to inhibit axon regeneration in C. elegans

“…In addition to rab-27 and the previously identified rab-6 . 2 [ 34 ], loss of rab-18 significantly decreases regeneration success, while loss of glo-1 leads to a modest increase in regeneration. Unlike other high-regenerating Rab mutants, glo-1 mutants specifically show an increase in full regeneration after 24 hours of recovery, though not an increase in the likelihood of regeneration initiation during that period ( Fig 6B and 6C ).…”

“…elegans , rab-6 . 2 was previously shown to affect regeneration [ 34 ], as was rab-27 function in neurons [ 8 ]. This work probed the function of RAB-27 outside the nervous system, revealing an unexpected role for DCV fusion in the intestine in regulation of axon regeneration.…”

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“…C. elegans provides an excellent system to probe the "rabome" for novel pathways affecting axon regeneration. In C. elegans, rab-6.2 was previously shown to affect regeneration [34], as was rab-27 function in neurons [8]. This work probed the function of RAB-27 outside the nervous system, revealing an unexpected role for DCV fusion in the intestine in regulation of axon regeneration.…”