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- 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- 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.
While modern society is inventing new ways to rid the body of accumulated toxins, ranging from detoxifying foods and drinks to sweating in the hot Finnish sauna, our body has already evolved its own spa, which cleans up the cells by breaking down and removing the damaged proteins and organelles. This process is called “autophagy” or “self-eating” and was discovered in the 1990s by the Japanese cell biologist Yohinori Ohsumi, who was the first to study the mechanism of autophagy and to identify the genes for this recycling process in cells. In 2016, he received the Nobel Prize for Medicine for his pioneering work [1]. 
 
Autophagy
 
The starting point for autophagy is a bowl-shaped membrane, the phagophore, which grows and eventually engulfs bits of cytoplasm, along with damaged cell parts and organelles. The resulting organelle, which from now on is called autophagosome, is subsequently delivered to a digestive compartment of the cell, the lysosome, for breakup and recycling of cellular components [2]. We initially learned of autophagy in the 1960s, from the work of Christian de Duve, who was the first to observe and recognize that the membrane structures containing cytoplasm had the capacity to digest parts of the intracellular content [3]. At that time, it was thought that autophagosomes were just garbage units, serving for non-specific breakdown of unwanted sludge. Now we know that autophagy is far more complex. One type of autophagy can attack and destroy invading viruses and bacteria [4]. In holometabolous insects, autophagy is essential for caterpillars to become butterflies [5]. During exercise, autophagy is required to support skeletal muscle plasticity [6], while activation of autophagy via caloric restriction increases the lifespan in several model organisms, including rodents [7]. 
 
The Influence of Autophagy on the Brain
 
Given the role of autophagy in keeping the cytoplasm clear of junk, it is hardly surprising that this process is particularly important for long-lived cells such as neurons.

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 [8]. 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 [9]. 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). 

 
Why do autophagosomes transport BDNF from the synapse to the neuronal cell body? Our research suggests that this movement serves to control synaptic connectivity in the central nervous system. Dendrites and especially axons extend relatively far from the neuronal soma. BDNF released by neighboring nerve cells is endocytosed and transported to the soma to instruct the receiving neuron to extend its arbor complexity, thereby increasing the number of synaptic sites in the more elaborated neurites. We suggest that autophagosomes provide protection during this ride by keeping the receptor-bound BDNF active. In this way, autophagosomes safely convoy growth signals to the cell nucleus, where their stimulate the formation of de-novo neuronal processes.  
 
The BDNF-dependent formation of autophagosomes in axons and their transport to the cell body of a neuron is part of a self-accelerating cycle because one target of incoming BDNF signals in nerve cells is the BDNF gene itself [9]. Attenuation in BDNF gene expression is known to have devastating consequences for neuronal survival and maturation [10] and impaired BDNF/TrkB signaling is reported to play a significant role in the pathogenesis of Alzheimer’s disease [11]. In our studies we found that mice that lack the AP-2 adaptor and, thus, are unable to convey the BDNF signals from the synapse to the cell body due to impaired autophagosome transport, suffer from severe neurodegeneration of the entorhinal cortex (fig.2), which is the first brain region affected by AD in human patients [12]. Thus, our research unravels a crucial role of autophagosomes for functional BDNF/TrkB signaling and suggests that conditions, which lead to autophagy malfunction, as for example during normal aging [13], might cause neurodegeneration not only as a result of defective protein degradation, but also due to the impaired transport of survival signals within nerve cells.
 
Outlook
 
Fascinating enough, food restriction is known to not only induce autophagy, but also to upregulate the levels of BDNF [14]. The mechanism by which reducing calories or fasting is able to elevate BDNF is not really well understood. The knowledge generated by our research and continued in my own laboratory opens a new avenue towards understanding of how BDNF/TrkB signaling is regulated by caloric restriction. Furthermore, our recent findings lay the groundwork for understanding neuropathological conditions in which neurotrophin signaling malfunctions and facilitate the identification of new therapeutic targets in neurodegeneration. 
 

Author
Natalia L. Kononenko1

Affiliation
1 University of Cologne, CECAD Excellence Cluster, Cologne, Germany

Contact
University of Cologne
CECAD Excellence Cluster
Cologne, Germany
n.kononenko@uni-koeln.de
 

References

1. Tooze, S.A., et al., Fundamental mechanisms deliver the Nobel Prize to Ohsumi. Traffic, 2017. 18(2): p. 93-95.
2. Levine, B. and D.J. Klionsky, Development by Self-Digestion: Molecular Mechanisms and Biological Functions of Autophagy. Developmental Cell, 2004. 6(4): p. 463-477.
3. de Duve, C. and R. Wattiaux, Functions of Lysosomes. Annual Review of Physiology 1966. 28: p. 435-492.
4. Huang, J. and J.H. Brumell, Bacteria-autophagy interplay: a battle for survival. Nat Rev Micro, 2014. 12(2): p. 101-114.
5. Gianluca, T., et al., Autophagy in Invertebrates: Insights Into Development, Regeneration and Body Remodeling. Current Pharmaceutical Design, 2008. 14(2): p. 116-125.
6. Neel, B.A., Y. Lin, and J.E. Pessin, Skeletal muscle autophagy: a new metabolic regulator. Trends in Endocrinology & Metabolism, 2013. 24(12): p. 635-643.
7. Madeo, F., et al., Essential role for autophagy in life span extension. The Journal of Clinical Investigation, 2015. 125(1): p. 85-93.
8. Menzies, F.M., et al., Autophagy and Neurodegeneration: Pathogenic Mechanisms and Therapeutic Opportunities. Neuron, 2017. 93(5): p. 1015-1034.
9. Kononenko, N.L., et al., Retrograde transport of TrkB-containing autophagosomes via the adaptor AP-2 mediates neuronal complexity and prevents neurodegeneration. Nature Communications, 2017. 8: p. 14819.
10. Ernfors, P., K.-F. Lee, and R. Jaenisch, Mice lacking brain-derived neurotrophic factor develop with sensory deficits. Nature, 1994. 368(6467): p. 147-150.
11. Dawbarn, D. and S.J. Allen, Neurotrophins and neurodegeneration. Neuropathology and Applied Neurobiology, 2003. 29(3): p. 211-230.
12. Khan, U.A., et al., Molecular drivers and cortical spread of lateral entorhinal cortex dysfunction in preclinical Alzheimer's disease. Nat Neurosci, 2014. 17(2): p. 304-311.
13. Rubinsztein, David C., G. Mariño, and G. Kroemer, Autophagy and Aging. Cell. 146(5): p. 682-695.
14. Duan, W., et al., Dietary restriction stimulates BDNF production in the brain and thereby protects neurons against excitotoxic injury. Journal of Molecular Neuroscience, 2001. 16(1): p. 1-12.

Overview of Autophagy

 

 

Contact

University of Cologne
Joseph-Stelzmann str. 26
50931 Cologne
Deutschland

Register now!

The latest information directly via newsletter.

To prevent automated spam submissions leave this field empty.