RIT2 regulates autophagy lysosomal pathway induction and protects against α-synuclein pathology in a cellular model of Parkinson's disease.

Substantial work has been devoted to better understand the contribution of the myriad of genes that may underly the development of Parkinson's disease (PD) and their role in disease etiology. The small GTPase Ras-like without CAAX2 (RIT2) is one such genetic risk factor, with one single nucleotide polymorphism in the RIT2 locus, rs12456492, having been associated with PD risk in multiple populations. While RIT2 has previously been shown to influence signaling pathways, dopamine transporter trafficking, and LRRK2 activity, its cellular function remains unclear.

Deletion of in adult mice impairs basal AMPA receptor transmission and LTP in hippocampal CA1 pyramidal neurons.

Leucine-rich repeat transmembrane (LRRTM) proteins are synaptic cell adhesion molecules that influence synapse formation and function. They are genetically associated with neuropsychiatric disorders, and via their synaptic actions likely regulate the establishment and function of neural circuits in the mammalian brain. Here, we take advantage of the generation of a and double conditional knockout mouse ( cKO) to examine the role of LRRTM1,2 at mature excitatory synapses in hippocampal CA1 pyramidal neurons.

The Retromer Supports AMPA Receptor Trafficking During LTP.

Alterations in the function of the retromer, a multisubunit protein complex that plays a specialized role in endosomal sorting, have been linked to Alzheimer's and Parkinson's diseases, yet little is known about the retromer's role in the mature brain. Using in vivo knockdown of the critical retromer component VPS35, we demonstrate a specific role for this endosomal sorting complex in the trafficking of AMPA receptors during NMDA-receptor-dependent LTP at mature hippocampal synapses. The impairment of LTP due to VPS35 knockdown was mechanistically independent of any role of the retromer in the production of Aβ from APP.

Chronic pain. Decreased motivation during chronic pain requires long-term depression in the nucleus accumbens.

Several symptoms associated with chronic pain, including fatigue and depression, are characterized by reduced motivation to initiate or complete goal-directed tasks. However, it is unknown whether maladaptive modifications in neural circuits that regulate motivation occur during chronic pain. Here, we demonstrate that the decreased motivation elicited in mice by two different models of chronic pain requires a galanin receptor 1-triggered depression of excitatory synaptic transmission in indirect pathway nucleus accumbens medium spiny neurons.

Retromer mediates a discrete route of local membrane delivery to dendrites.

A fundamental and still largely unresolved question is how neurons achieve rapid delivery of selected signaling receptors throughout the elaborate dendritic arbor. Here we show that this requires a conserved sorting machinery called retromer. Retromer-associated endosomes are distributed within dendrites in ∼2 μm intervals and supply frequent membrane fusion events into the dendritic shaft domain immediately adjacent to (<300 nm from) the donor endosome and typically without full endosome discharge.

SNX27 mediates retromer tubule entry and endosome-to-plasma membrane trafficking of signalling receptors.

Endocytic sorting of signalling receptors between recycling and degradative pathways is a key cellular process controlling the surface complement of receptors and, accordingly, the cell's ability to respond to specific extracellular stimuli. The β2 adrenergic receptor (β2AR) is a prototypical seven-transmembrane signalling receptor that recycles rapidly and efficiently to the plasma membrane after ligand-induced endocytosis. β2AR recycling is dependent on the receptor's carboxy-terminal PDZ ligand and Rab4.

Sequence-dependent sorting of recycling proteins by actin-stabilized endosomal microdomains.

The functional consequences of signaling receptor endocytosis are determined by the endosomal sorting of receptors between degradation and recycling pathways. How receptors recycle efficiently, in a sequence-dependent manner that is distinct from bulk membrane recycling, is not known. Here, in live cells, we visualize the sorting of a prototypical sequence-dependent recycling receptor, the beta-2 adrenergic receptor, from bulk recycling proteins and the degrading delta-opioid receptor.

SNX27 mediates PDZ-directed sorting from endosomes to the plasma membrane.

Postsynaptic density 95/discs large/zonus occludens-1 (PDZ) domain-interacting motifs, in addition to their well-established roles in protein scaffolding at the cell surface, are proposed to act as cis-acting determinants directing the molecular sorting of transmembrane cargo from endosomes to the plasma membrane. This hypothesis requires the existence of a specific trans-acting PDZ protein that mediates the proposed sorting operation in the endosome membrane. Here, we show that sorting nexin 27 (SNX27) is required for efficient PDZ-directed recycling of the beta(2)-adrenoreceptor (beta(2)AR) from early endosomes.

N-terminal tyrosine residues within the potassium channel Kir3 modulate GTPase activity of Galphai.

trkB activation results in tyrosine phosphorylation of N-terminal Kir3 residues, decreasing channel activation. To determine the mechanism of this effect, we reconstituted Kir3, trkB, and the mu opioid receptor in Xenopus oocytes. Activation of trkB by BDNF (brain-derived neurotrophic factor) accelerated Kir3 deactivation following termination of mu opioid receptor signaling.