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LRRK2 polymorphisms (G2019S/N2081D) that increase susceptibility to Parkinson's disease and Crohn's disease (CD) lead to LRRK2 kinase hyperactivity and suppress autophagy. This connection suggests that LRRK2 kinase inhibition, a therapeutic strategy being explored for Parkinson's disease, may also benefit patients with CD. Paneth cell homeostasis is tightly regulated by autophagy, and their dysfunction is a precursor to gut inflammation in CD. Here, we found that patients with CD and mice carrying hyperactive LRRK2 polymorphisms developed Paneth cell dysfunction. We also found that LRRK2 kinase can be activated in the context of interactions between genes (genetic autophagy deficiency) and the environment (cigarette smoking). Unexpectedly, lamina propria immune cells were the main intestinal cell types that express LRRK2, instead of Paneth cells as previously suggested. We showed that LRRK2-mediated pro-inflammatory cytokine release from phagocytes impaired Paneth cell function, which was rescued by LRRK2 kinase inhibition through activation of autophagy. Together, these data suggest that LRRK2 kinase inhibitors maintain Paneth cell homeostasis by restoring autophagy and may represent a therapeutic strategy for CD. Editor's summary: Specific variants in the leucine-rich repeat kinase 2 (LRRK2) gene are associated with increased susceptibility to Crohn's disease (CD), but how LRRK2 contributes to the pathogenesis of CD is not fully understood. Using mice harboring LRRK2 risk alleles, Sun et al. found that hyperactive LRRK2 in macrophages led to impaired autophagy and Paneth cell dysfunction. Pathogenic LRRK2 kinase activity could also be triggered by deficiency of the autophagy gene ATG16L1 in combination with cigarette smoke and rescued by an LRRK2 inhibitor. Together, these findings identify a Paneth cell–extrinsic pathway by which hyperactive LRRK2 interferes with autophagy and intestinal epithelial homeostasis. —Claire Olingy [ABSTRACT FROM AUTHOR]

In neurons, lysosomes, which degrade membrane and cytoplasmic components, are thought to primarily reside in somatic and axonal compartments, but there is little understanding of their distribution and function in dendrites. Here, we used conventional and two-photon imaging and electron microscopy to show that lysosomes traffic bidirectionally in dendrites and are present in dendritic spines. We find that lysosome inhibition alters their mobility and also decreases dendritic spine number. Furthermore, perturbing microtubule and actin cytoskeletal dynamics has an inverse relationship on the distribution and motility of lysosomes in dendrites. We also find trafficking of lysosomes is correlated with synaptic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptors. Strikingly, lysosomes traffic to dendritic spines in an activity-dependent manner and can be recruited to individual spines in response to local activation. These data indicate the position of lysosomes is regulated by synaptic activity and thus plays an instructive role in the turnover of synaptic membrane proteins.

The trafficking of AMPA receptors (AMPARs) to and from synapses is crucial for synaptic plasticity. Previous work has demonstrated that AMPARs undergo activity-dependent ubiquitination by the E3 ubiquitin ligase Nedd4-1, which promotes their internalization and degradation in lysosomes. Here, we define the molecular mechanisms involved in ubiquitination and deubiquitination of AMPARs. We report that Nedd4-1 is rapidly redistributed to dendritic spines in response to AMPAR activation and not in response to NMDA receptor (NMDAR) activation in cultured rat neurons. In contrast, NMDAR activation directly antagonizes Nedd4-1 function by promoting the deubiquitination of AMPARs. We show that NMDAR activation causes the rapid dephosphorylation and activation of the deubiquitinating enzyme (DUB) USP8. Surface AMPAR levels and synaptic strength are inversely regulated by Nedd4-1 and USP8. Strikingly, we show that homeostatic downscaling of synaptic strength is accompanied by an increase and decrease in Nedd4-1 and USP8 protein levels, respectively. Furthermore, we show that Nedd4-1 is required for homeostatic loss of surface AMPARs and downscaling of synaptic strength. This study provides the first mechanistic evidence for rapid and opposing activity-dependent control of a ubiquitin ligase and DUB at mammalian CNS synapses. We propose that the dynamic regulation of these opposing forces is critical in maintaining synapses and scaling them during homeostatic plasticity. [ABSTRACT FROM AUTHOR]

Previous studies on Syrian hamster pups (< 30 days old) have shown that several hippocampal mechanisms underlying memory formation can be activated, including long-term depression (LTD) and long-term potentiation (LTP). But it is not known if synaptic mechanisms for establishing LTD are present in adult hamsters old enough to hibernate (i.e., greater than 60 days of age). Adaptations providing neuroprotection in hibernating hamsters involve a variety of cellular modifications that minimize energy expenditure. One such adaptation could be a reduction of the variety of plasticity mechanisms. In this study, we examined this possibility by testing the hypothesis that LTD could be generated in hamsters able to hibernate. For this, slices were immersed in a buffer containing 2.5 mM Ca++ and 1.5 mM Mg++. We measured population spike (PS) amplitude before and after a 15 min period of low frequency stimulation (LFS) of 900 shocks in slices from hamsters on a 14:10 Light:Dark cycle, housed at 22 ± 2°C. In six slices from 5 hamsters, PS amplitude decreased by 14.7 ± 2.7% following LFS. PS amplitude subsequently increased by 41.5 ± 6.3% following tetanus, demonstrating LTP and slice viability. These findings indicate that LTD can he elicited in slices from adult hamsters. Thus, like non-hibernating rodent species, the adult hamster appears to have a complete set of hippocampal neural mechanisms to support memory formation. [ABSTRACT FROM AUTHOR]