AP-1γ2 is an adaptor protein 1 variant required for endosome-to-Golgi trafficking of the mannose-6-P receptor (CI-MPR) and ATP7B copper transporter.

Selective retrograde transport from endosomes back to the trans-Golgi network (TGN) is important for maintaining protein homeostasis, recycling receptors, and returning molecules that were transported to the wrong compartments. Two important transmembrane proteins directed to this pathway are the Cation-Independent Mannose-6-phosphate receptor (CI-MPR) and the ATP7B copper transporter. Among CI-MPR functions is the delivery of acid hydrolases to lysosomes, while ATP7B facilitates the transport of cytosolic copper ions into organelles or the extracellular space. Precise subcellular localization of CI-MPR and ATP7B is essential for the proper functioning of these proteins. This study shows that both CI-MPR and ATP7B interact with a variant of the clathrin adaptor 1 (AP-1) complex that contains a specific isoform of the γ-adaptin subunit called γ2. Through synchronized anterograde trafficking and cell-surface uptake assays, we demonstrated that AP-1γ2 is dispensable for ATP7B and CI-MPR exit from the TGN while being critically required for ATP7B and CI-MPR retrieval from endosomes to the TGN. Moreover, AP-1γ2 depletion leads to the retention of endocytosed CI-MPR in endosomes enriched in retromer complex subunits. These data underscore the importance of AP-1γ2 as a key component in the sorting and trafficking machinery of CI-MPR and ATP7B, highlighting its essential role in the transport of proteins from endosomes.

The Rab11-regulated endocytic pathway and BDNF/TrkB signaling: Roles in plasticity changes and neurodegenerative diseases.

Neurons are highly polarized cells that rely on the intracellular transport of organelles. This process is regulated by molecular motors such as dynein and kinesins and the Rab family of monomeric GTPases that together help move cargo along microtubules in dendrites, somas, and axons. Rab5-Rab11 GTPases regulate receptor trafficking along early-recycling endosomes, which is a process that determines the intracellular signaling output of different signaling pathways, including those triggered by BDNF binding to its tyrosine kinase receptor TrkB. BDNF is a well-recognized neurotrophic factor that regulates experience-dependent plasticity in different circuits in the brain. The internalization of the BDNF/TrkB complex results in signaling endosomes that allow local signaling in dendrites and presynaptic terminals, nuclear signaling in somas and dynein-mediated long-distance signaling from axons to cell bodies. In this review, we briefly discuss the organization of the endocytic pathway and how Rab11-recycling endosomes interact with other endomembrane systems. We further expand upon the roles of the Rab11-recycling pathway in neuronal plasticity. Then, we discuss the BDNF/TrkB signaling pathways and their functional relationships with the postendocytic trafficking of BDNF, including axonal transport, emphasizing the role of BDNF signaling endosomes, particularly Rab5-Rab11 endosomes, in neuronal plasticity. Finally, we discuss the evidence indicating that the dysfunction of the early-recycling pathway impairs BDNF signaling, contributing to several neurodegenerative diseases.

Axonal PPARγ promotes neuronal regeneration after injury.

PPARγ is a ligand-activated nuclear receptor best known for its involvement in adipogenesis and glucose homeostasis. PPARγ activity has also been associated with neuroprotection in different neurological disorders, but the mechanisms involved in PPARγ effects in the nervous system are still unknown. Here we describe a new functional role for PPARγ in neuronal responses to injury. We found both PPAR transcripts and protein within sensory axons and observed an increase in PPARγ protein levels after sciatic nerve crush. This was correlated with increased retrograde transport of PPARγ after injury, increased association of PPARγ with the molecular motor dynein, and increased nuclear accumulation of PPARγ in cell bodies of sensory neurons. Furthermore, PPARγ antagonists attenuated the response of sensory neurons to sciatic nerve injury, and inhibited axonal growth of both sensory and cortical neurons in culture. Thus, axonal PPARγ is involved in neuronal injury responses required for axonal regeneration. Since PPARγ is a major molecular target of the thiazolidinedione (TZD) class of drugs used in the treatment of type II diabetes, several pharmaceutical agents with acceptable safety profiles in humans are available. Our findings provide motivation and rationale for the evaluation of such agents for efficacy in central and peripheral nerve injuries.