Progranulin and TMEM106B: when two become wan

Mutations in GRN, which encodes progranulin, are a common cause of familial frontotemporal dementia (FTD). FTD is a devastating disease characterised by neuronal loss in the frontal and temporal lobes that leads to changes in personality, behaviour and language. There are no effective treatments for this complex condition. TMEM106B is a well‐recognised risk factor for FTD caused by GRN mutation. While the specific relationship between progranulin and TMEM106B is unclear, it is well established that they are both required for correct lysosome function and trafficking. Elegant experiments have suggested that increased risk for FTD is due to elevated levels of TMEM106B (Nicholson et al, 2013; Gallagher et al, 2017). Therefore, recent work has explored the therapeutic potential of reducing TMEM106B levels, with initial results looking encouraging, as crossing a Grn‐deficient mouse to a Tmem106b knockout showed a rescue in FTD‐related behavioural defects and specific aspects of lysosome dysfunction (Klein et al, 2017). However, three independent studies in this issue report that completely removing Tmem106b from Grn knockout mice leads to clear exacerbation of phenotypes, causing severe motor deficits, neurodegeneration and enhanced lysosome abnormalities and gliosis. Remarkably, the double knockout mice also develop TDP‐43 pathology—a hallmark of FTD patients with GRN mutations that have not been consistently observed in either of the single knockouts. These concurrent publications that all reach the same surprising but definitive conclusion are a cautionary tale in the control of TMEM106B levels as a potential therapeutic for FTD. They also re‐ignite the debate as to whether loss or gain of TMEM106B function is critical for altering FTD risk

Mammalian phosphatidylinositol 4-kinases as modulators of membrane trafficking and lipid signaling networks.

The four mammalian phosphatidylinositol 4-kinases modulate inter-organelle lipid trafficking, phosphoinositide signalling and intracellular vesicle trafficking. In addition to catalytic domains required for the synthesis of PI4P, the phosphatidylinositol 4-kinases also contain isoform-specific structural motifs that mediate interactions with proteins such as AP-3 and the E3 ubiquitin ligase Itch, and such structural differences determine isoform-specific roles in membrane trafficking. Moreover, different permutations of phosphatidylinositol 4-kinase isozymes may be required for a single cellular function such as occurs during distinct stages of GPCR signalling and in Golgi to lysosome trafficking. Phosphatidylinositol 4-kinases have recently been implicated in human disease. Emerging paradigms include increased phosphatidylinositol 4-kinase expression in some cancers, impaired functioning associated with neurological pathologies, the subversion of PI4P trafficking functions in bacterial infection and the activation of lipid kinase activity in viral disease. We discuss how the diverse and sometimes overlapping functions of the phosphatidylinositol 4-kinases present challenges for the design of isoform-specific inhibitors in a therapeutic context

Electromagnetic Structure of the Pion

In this work, we analyze the electromagnetic structure of the pion. We calculate its electromagnetic radius and electromagnetic form factor in low and intermediate momentum range. Such observables are determined by means of a theoretical model that takes into account the constituent quark and antiquark of the pion within the formalism of light-front field theory. In particular, we consider a nonsymmetrical vertex in this model, with which we calculate the electromagnetic form factor of the pion in an optimized way, so that we obtain a value closer to the experimental charge radius of the pion. The theoretical calculations are also compared with the most recent experimental data involving the pion electromagnetic form factor and the results show very good agreement.Comment: Paper with 4 pages, 1 figure, presented in XII HADRON PHYSICS Conference - to appear in AIP Conference Proceeding

A novel synaptopathy-defective synaptic vesicle protein trafficking in the mutant CHMP2B mouse model of frontotemporal dementia

Mutations in the ESCRT-III subunit CHMP2B cause frontotemporal dementia (FTD) and lead to impaired endolysosomal trafficking and lysosomal storage pathology in neurons. We investigated the effect of mutant CHMP2B on synaptic pathology, as ESCRT function was recently implicated in the degradation of synaptic vesicle (SV) proteins. We report here that expression of C-terminally truncated mutant CHMP2B results in a novel synaptopathy. This unique synaptic pathology is characterised by selective retention of presynaptic SV trafficking proteins in aged mutant CHMP2B transgenic mice, despite significant loss of postsynaptic proteins. Furthermore, ultrastructural analysis of primary cortical cultures from transgenic CHMP2B mice revealed a significant increase in the number of presynaptic endosomes, while neurons expressing mutant CHMP2B display defective SV recycling and alterations to functional SV pools. Therefore, we reveal how mutations in CHMP2B affect specific presynaptic proteins and SV recycling, identifying CHMP2B FTD as a novel synaptopathy. This novel synaptopathic mechanism of impaired SV physiology may be a key early event in multiple forms of FTD, since proteins that mediate the most common genetic forms of FTD all localise at the presynapse

Iron Implantation in Presolar Supernova Grains

We consider the potential of measured iron isotopic ratios within presolar grains from supernovae (as discovered in meteorites) for identifying the gas from which the grains condensed. We show that although iron isotopic ratios vary dramatically with radial coordinate in the initial supernova, it seems likely that the concentration of iron that thermally condenses in SiC grains within the supernova interior may be smaller than the concentration that will later be implanted by high-speed grain-gas collisions following the penetration of the reverse shock into the supernova flow. In that case, the Fe isotopic composition is much altered. We propose that the 58Fe richness that is very evident in the three SiC grains analyzed to date is the result of ion implantation during the grain’s rapid radial motion through the shocked and decelerated overlying supernova gas that is 58Fe-rich. We point to other likely applications of this same idea and speculate that only the dominant isotopes of the SiC grains, namely 28Si and 12C, can be safely assumed to be initial thermal condensate. We conclude that a violent period of implantation plus sputtering has overprinted the initial thermal condensate. If correct, this points to a new technique for sampling the velocity mixing within young supernova remnants

Modified bacterial reaction centers

Pigments of borohydride-treated reaction centers of Rhodobacter sphaeroides R 26 and Rhodopseudomonas viridis were analyzed by HPLC with polychromatic detection. In both species, pigment composition and contents were unchanged. Reaction centers from Rhodobacter sphaeroides R26 were prepared in which bacteriochlorophylls (BA,B) and bacteriopheophytins (HA,B) were exchanged with their potential borohydride products reduced at C-31. [3-Hydroxyethyl]-BChl a exchanges selectively into the BA,B pockets, and 31-OH-BPh a to the HA,B pockets. Stable reaction centers are obtained in both cases. A comparison of the absorption and circular dichroism spectra of reaction centers after exchange with 31-OH pigments, and of borohydride-modified reaction centers, reveal distinct differences. It is concluded that during borohydride reduction none of the pigments is chemically modified or extracted from the reaction centers

Key Physiological Parameters Dictate Triggering of Activity-Dependent Bulk Endocytosis in Hippocampal Synapses

To maintain neurotransmission in central neurons, several mechanisms are employed to retrieve synaptically exocytosed membrane. The two major modes of synaptic vesicle (SV) retrieval are clathrin-mediated endocytosis and activity-dependent bulk endocytosis (ADBE). ADBE is the dominant SV retrieval mode during intense stimulation, however the precise physiological conditions that trigger this mode are not resolved. To determine these parameters we manipulated rat hippocampal neurons using a wide spectrum of stimuli by varying both the pattern and duration of stimulation. Using live-cell fluorescence imaging and electron microscopy approaches, we established that stimulation frequency, rather than the stimulation load, was critical in the triggering of ADBE. Thus two hundred action potentials, when delivered at high frequency, were sufficient to induce near maximal bulk formation. Furthermore we observed a strong correlation between SV pool size and ability to perform ADBE. We also identified that inhibitory nerve terminals were more likely to utilize ADBE and had a larger SV recycling pool. Thus ADBE in hippocampal synaptic terminals is tightly coupled to stimulation frequency and is more likely to occur in terminals with large SV pools. These results implicate ADBE as a key modulator of both hippocampal neurotransmission and plasticity

Dissecting Galaxy Formation: II. Comparing Substructure in Pure Dark Matter and Baryonic Models

We compare the substructure evolution in pure dark matter (DM) halos with those in the presence of baryons (PDM and BDM). The prime halos have been analyzed by Romano-Diaz et al (2009). Models have been evolved from identical initial conditions using Constrained Realizations, including star formation and feedback. A comprehensive catalog of subhalos has been compiled and properties of subhalos analyzed in the mass range of 10^8 Mo - 10^11 Mo. We find that subhalo mass functions are consistent with a single power law, M_sbh^{alpha}, but detect a nonnegligible shift between these functions, alpha -0.86 for the PDM, and -0.98 for the BDM. Overall, alpha const. in time with variations of +-15%. Second, we find that the radial mass distribution of subhalos can be approximated by a power law, R^{gamma} with a steepening around the radius of a maximal circular velocity, Rvmax, in the prime halos. Gamma ~-1.5 for the PDM and -1 for the BDM, inside Rvmax, and is steeper outside. We detect little spatial bias between the subhalo populations and the DM of the main halos. The subhalo population exhibits much less triaxiality with baryons, in tandem with the prime halo. Finally, we find that, counter-intuitively, the BDM population is depleted at a faster rate than the PDM one within the central 30kpc of the prime. Although the baryons provide a substantial glue to the subhalos, the main halos exhibit the same trend. This assures a more efficient tidal disruption of the BDM subhalos. This effect can be reversed for a more efficient feedback from stellar evolution and supermassive black holes, which will expel baryons from the center and decrease the concentration of the prime halo. We compare our results with via Lactea and Aquarius simulations and other published results.Comment: 12 pages, 9 figures, to be published by the Astrophysical Journa

C9orf72 repeat expansions cause neurodegeneration in Drosophila through arginine-rich proteins

An expanded GGGGCC repeat in C9orf72 is the most common genetic cause of frontotemporal dementia and amyotrophic lateral sclerosis. A fundamental question is whether toxicity is driven by the repeat RNA itself and/or by dipeptide repeat proteins generated by repeat-associated, non-ATG translation. To address this question we developed in vitro and in vivo models to dissect repeat RNA and dipeptide repeat protein toxicity. Expression of pure repeats in Drosophila caused adult-onset neurodegeneration attributable to poly-(glycine-arginine) proteins. Thus, expanded repeats promoted neurodegeneration through neurotoxic proteins. Expression of individual dipeptide repeat proteins with a non-GGGGCC RNA sequence showed both poly-(glycine-arginine) and poly-(proline-arginine) proteins caused neurodegeneration. These findings are consistent with a dual toxicity mechanism, whereby both arginine-rich proteins and repeat RNA contribute to C9orf72-mediated neurodegeneration