The Reelin receptor ApoER2 is a cargo for the adaptor protein complex AP-4: Implications for Hereditary Spastic Paraplegia.

Adaptor protein complex 4 (AP-4) is a heterotetrameric complex that promotes export of selected cargo proteins from the trans-Golgi network. Mutations in each of the AP-4 subunits cause a complicated form of Hereditary Spastic Paraplegia (HSP). Herein, we report that ApoER2, a receptor in the Reelin signaling pathway, is a cargo of the AP-4 complex. We identify the motif ISSF/Y within the ApoER2 cytosolic domain as necessary for interaction with the canonical signal-binding pocket of the µ4 (AP4M1) subunit of AP-4. AP4E1- knock-out (KO) HeLa cells and hippocampal neurons from Ap4e1-KO mice display increased co-localization of ApoER2 with Golgi markers. Furthermore, hippocampal neurons from Ap4e1-KO mice and AP4M1-KO human iPSC-derived cortical i3Neurons exhibit reduced ApoER2 protein expression. Analyses of biosynthetic transport of ApoER2 reveal differential post-Golgi trafficking of the receptor, with lower axonal distribution in KO compared to wild-type neurons, indicating a role of AP-4 and the ISSF/Y motif in the axonal localization of ApoER2. Finally, analyses of Reelin signaling in mouse hippocampal and human cortical KO neurons show that AP4 deficiency causes no changes in Reelin-dependent activation of the AKT pathway and only mild changes in Reelin-induced dendritic arborization, but reduces Reelin-induced ERK phosphorylation, CREB activation, and Golgi deployment. This work thus establishes ApoER2 as a novel cargo of the AP-4 complex, suggesting that defects in the trafficking of this receptor and in the Reelin signaling pathway could contribute to the pathogenesis of HSP caused by mutations in AP-4 subunits.

The Reelin Receptor ApoER2 is a Cargo for the Adaptor Protein Complex AP-4: Implications for Hereditary Spastic Paraplegia.

Adaptor protein complex 4 (AP-4) is a heterotetrameric complex that promotes protein export from the trans -Golgi network. Mutations in each of the AP-4 subunits cause a complicated form of Hereditary Spastic Paraplegia (HSP). Herein, we report that ApoER2, a receptor in the Reelin signaling pathway, is a cargo of the AP-4 complex. We identify the motif ISSF/Y within the ApoER2 cytosolic domain as necessary for interaction with the canonical signal-binding pocket of the µ4 (AP4M1) subunit of AP-4. AP4E1 -knock-out (KO) HeLa cells and hippocampal neurons from Ap4e1 -KO mice display increased Golgi localization of ApoER2. Furthermore, hippocampal neurons from Ap4e1 -KO mice and AP4M1 -KO human iPSC-derived cortical i3Neurons exhibit reduced ApoER2 protein expression. Analyses of biosynthetic transport of ApoER2 reveal differential post-Golgi trafficking of the receptor, with lower axonal distribution in KO compared to wild-type neurons, indicating a role of AP-4 and the ISSF/Y motif in the axonal localization of ApoER2. Finally, analyses of Reelin signaling in mouse hippocampal and human cortical KO neurons show that AP4 deficiency causes no changes in Reelin-dependent activation of the AKT pathway and only mild changes in Reelin-induced dendritic arborization, but reduces Reelin-induced ERK phosphorylation, CREB activation, and Golgi deployment. Altogether, this work establishes ApoER2 as a novel cargo of the AP-4 complex, suggesting that defects in the trafficking of this receptor and in the Reelin signaling pathway could contribute to the pathogenesis of HSP caused by mutations in AP-4 subunits.

Limnological response from high-altitude wetlands to the water supply in the Andean Altiplano.

The Andean Altiplano-Puna is located at an elevation of approximately 4000 m.a.s.l. and is delineated by the Western and the Eastern Andes Cordillera. The high-altitude wetlands (HAWs) in the Central Andes are unique ecosystems located in the Altiplano that provide many ecosystem services. The objective of this study was to characterize the spatial heterogeneity of the environmental conditions associated with varying hydrology of the HAW, Salar de Tara, in the Andean Altiplano. Sediment samples of up to 20 cm in depth were obtained from various salt flat sub-environments. The samples were analyzed using proxies for mineralogical and chemical composition, thermal analysis, and magnetic susceptibility. Diatom and ostracod communities were also identified and analyzed. The results reflected changes in the geochemistry, carbon content, mineralogy, and magnetic properties of the sediments that can be explained by variations in the sources of water input to the Salar de Tara. The sub-environments depend on the supply of water via the groundwater recharge of springs adjacent to the streamflow from the Zapaleri River, which promotes greater diversity and richness of genera. Our results suggest that water extraction at industrial levels greatly impacts the persistence of hydrologically connected HAWs, which concentrate a worldwide interest in brine mining.

Aquatic community structure as sentinel of recent environmental changes unraveled from lake sedimentary records from the Atacama Desert, Chile.

The Atacama Desert (21-26°S) is currently one of the driest places on Earth and metal(loid)s are of special concern for this region, which hosts the largest-known porphyry copper deposits produced in Chile. Evidence of past environmental conditions is commonly preserved in natural archives, such as lacustrine sediments. Sediment records obtained from Inca Coya Lake (22°20'S-68°35'W, 2534 m.a.s.l.), a small lake located in the Atacama Desert, reflected the evolution of regional mining activity during the 20th century and sedimentation associated with decadal climate variability. We studied the aquatic community structure changes recorded in sediment records from Inca Coya Lake. By analysis of magnetic properties (susceptibility, hysteresis curves and Curie temperatures), grain size and geochemical composition of the sediments, we identified environmental periods and changes in the community of benthic and planktonic organisms (diatoms and diapausing egg bank). We identified three detrital episodes that we interpret as dry/wet phases during the last 90 years associated with the increase of flash flood events promoting hypoxia oscillations; anthropogenic (mining activity) signals were also identified. Invertebrate community structure (primary consumers) reflected the metal exposure, measured as changes in assemblage composition through species turnover. Diatom community composition was best associated with variables related to wetter/drier alternation and consequent changes in oxygen availability. Bioindicators analyzed (diatoms, diapausing egg bank and invertebrate community) demonstrated to be excellent indicators of the bioavailability of compounds in the aquatic ecosystem of Inca Coya Lake, allowing the environmental impact assessment of the water resources due to flash floods and mining activity in the driest desert of the world.