One-Way Ticket for a Ride
A Novel Role for Autophagosomes in the Brain
- Fig- 1: Hypothetical model for the role of AP-2 in retrograde transport of TrkB-containing autophagosomes in neurons. In WT neurons, AP-2 via its association with LC3 and p150Glued mediates retrograde transport of BDNF/ TrkB-containing amphisomes (late-stage autophagosomes post-fusion with Rab7-positive late endosomes) to the cell body, where TrkB signaling regulates transcription of activity-dependent genes in the nucleus. In the absence of AP-2 (KO) TrkB endocytosis proceeds, however BDNF/ TrkB-mediated signaling is defective due to impaired retrograde transport of BDNF/ TrkB-containing autophagosomes. Stalled amphisomes in neurites of AP-2 KO neurons cause axonal swellings and underlie neurodegeneration. Reproduced from ref. 9.
- Fig. 2: Neurodegeneration in mice lacking neuronal AP-2µ. Temporal progression of medial entorhinal cortex (MEC) degeneration in AP-2µ KO mice, captured by Nissl-staining of brains at postnatal day 4 (P4) (a), P7 (b) and P14 (c,d). Black arrows in (d) mark the spongiform neurodegeneration. Scale bars (a,b) 300µm, (c) 400µm, (d) 80 µm. Reproduced from ref. 9.
The post-mitotic nature of neurons predisposes them to the accumulation of unfavorable proteins and damaged organelles that are otherwise diluted by cell division in replicating cells. The fact that autophagy is crucial for brain well-being is supported by scientific discoveries of the last decade, highlighting defective autophagy as one of pathological causes of neurodegenerative disorders, including Alzheimer’s (AD), Parkinson’s and Huntington’s diseases . In the context of Alzheimer’s disease, scientists used to assign autophagosomes the role of degrading and clearing aggregated proteins to counteract the disease. However, our own recent research at the Leibniz Institute for Molecular Pharmacology (FMP) in Berlin and at the CECAD Excellence Cluster at the University of Cologne identified a novel function for autophagosomes in neurons. We have found that autophagosomes function as taxis for pro-survival signals such as brain-derived neurotrophic factor (BDNF), a protein within nerve cells that keeps them functioning optimally and contributes to their growth, as well as to the formation of de-novo neuronal connections. Low levels of BDNF and its receptor TrkB are linked to many neurodegenerative conditions, including AD. Now our research adds a novel aspect in BDNF-related pathology. Our work shows that fewer ‘taxis’ or taxis without the motor will lead to reduced growth promoting signals arriving at the cell body, the so-called soma, and, in turn, the death of nerve cells . Adaptor protein complex-2 (AP-2), an essential protein complex previously thought to function exclusively in clathrin-mediated endocytosis, provides taxis with the motor power in neurons. AP-2 fulfills this task by association with the autophagy protein LC3 (microtubule-associated protein 1A/1B-light chain 3) and the p150Glued – an activator of the motor protein dynein. Deletion of neuronal AP-2 in mice uncouples the autophagosomes from their motors and leads to the loss of neuronal complexity (fig. 1).
Natalia L. Kononenko1
1 University of Cologne, CECAD Excellence Cluster, Cologne, Germany
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