Glycolytically impaired Drosophila glial cells fuel neural metabolism via ß-oxidation.

Neuronal function is highly energy demanding and thus requires efficient and constant metabolite delivery by glia. Drosophila glia are highly glycolytic and provide lactate to fuel neuronal metabolism. Flies are able to survive for several weeks in the absence of glial glycolysis. Here, we study how Drosophila glial cells maintain sufficient nutrient supply to neurons under conditions of impaired glycolysis. We show that glycolytically impaired glia rely on mitochondrial fatty acid breakdown and ketone body production to nourish neurons, suggesting that ketone bodies serve as an alternate neuronal fuel to prevent neurodegeneration. We show that in times of long-term starvation, glial degradation of absorbed fatty acids is essential to ensure survival of the fly. Further, we show that Drosophila glial cells act as a metabolic sensor and can induce mobilization of peripheral lipid stores to preserve brain metabolic homeostasis. Our study gives evidence of the importance of glial fatty acid degradation for brain function, and survival, under adverse conditions in Drosophila.

Ecdysone regulates Drosophila wing disc size via a TORC1 dependent mechanism.

Most cells in a developing organ stop proliferating when the organ reaches a correct, final size. The underlying molecular mechanisms are not understood. We find that in Drosophila the hormone ecdysone controls wing disc size. To study how ecdysone affects wing size, we inhibit endogenous ecdysone synthesis and feed larvae exogenous ecdysone in a dose-controlled manner. For any given ecdysone dose, discs stop proliferating at a particular size, with higher doses enabling discs to reach larger sizes. Termination of proliferation coincides with a drop in TORC1, but not Dpp or Yki signaling. Reactivating TORC1 bypasses the termination of proliferation, indicating that TORC1 is a main downstream effector causing proliferation termination at the maximal ecdysone-dependent size. Experimental manipulation of Dpp or Yki signaling can bypass proliferation termination in hinge and notum regions, but not the pouch, suggesting that the mechanisms regulating proliferation termination may be distinct in different disc regions.

Hereditary defect of cobalamin metabolism with adolescence onset resembling multiple sclerosis: 41-year follow up in two cases.

The cblC defect is the most common inborn error of cobalamin (Cbl) metabolism. Clinical severity and presentation of the cblC defect ranges from death to mild disability. Only 71 cases of late-onset cblC defect have been described in the literature. We provide the 41-year follow up of two siblings with a late-onset cblC defect, first described after initial diagnosis in 1996. While one of the siblings showed initial symptoms resembling multiple sclerosis with a good response to corticosteroids, the other sister showed only subclinical signs of the disease. The course of the first case was characterized by a severe deterioration and intensive-care therapy after respiratory failure. After diagnoses and Cbl treatment, the patient survived and showed a pronounced improvement of the symptoms. Both sisters have an active life and gave birth to healthy children. The reason for the initial improvement after corticosteroids could not be explained by the classical metabolic pathways of Cbl. Recent studies have suggested that Cbl plays an important role as a regulator of the balance between neurotrophic and neurotoxic factors in the central and peripheral nervous system (CNS and PNS). This first long-term follow up revealed that ultra-high-dose intramuscular Hydroxocobalamin (OH-Cbl) treatment can effectively protect patients from disease progression. It underlines the importance of diagnostic vigilance and laboratory work up even in cases without typical hematologic signs of Cbl deficiency. Cbl-related diseases are often a chameleon and must always be considered in the differential of demyelinating diseases of the PNS and CNS. The case supports the theory that it is not only the classical biochemical pathways that play a key role in Cbl deficiency, especially with regard to neurological symptoms.

Drosophila ZDHHC8 palmitoylates scribble and Ras64B and controls growth and viability.

Palmitoylation is an important posttranslational modification regulating diverse cellular functions. Consequently, aberrant palmitoylation can lead to diseases such as neuronal disorders or cancer. In humans there are roughly one hundred times more palmitoylated proteins than enzymes catalyzing palmitoylation (palmitoyltransferases). Therefore, it is an important challenge to establish the links between palmitoyltransferases and their targets. From publicly available data, we find that expression of human ZDHHC8 correlates significantly with cancer survival. To elucidate the organismal function of ZDHHC8, we study the Drosophila ortholog of hZDHHC8, CG34449/dZDHHC8. Knockdown of dZDHHC8 causes tissue overgrowth while dZDHHC8 mutants are larval lethal. We provide a list of 159 palmitoylated proteins in Drosophila and present data suggesting that scribble and Ras64B are targets of dZDHHC8.

Flies Eat Their Veggies to Survive the Cold.

Although Drosophila melanogaster fruit flies are cold-blooded, they can survive a wide range of temperatures. In this issue of Developmental Cell, Brankatschk et al. (2018) discover a mechanism by which flies extend their viable temperature range by altering their diet in response to environmental temperature.

Detection of JC virus archetype in cerebrospinal fluid in a MS patient with dimethylfumarate treatment without lymphopenia or signs of PML.

We report a 76-year-old MS patient, treated with DMF for 3 years. Lymphocytes never showed values below 1240/µl. CSF analysis revealed 1,988,880 copies/ml of JCV-DNA, JCV-DNA was detectable in serum and anti-JCV-antibody in CSF and serum were highly positive. Stratify®-JCV-test was positive. CD8-positive T-lymphocytes were reduced. Therapy with mefloquine, mirtazapine and cidofovir resulted in complete elimination of the virus in serum and 90% reduction of viral load in CSF. This case shows that despite careful monitoring for lymphopenia JCV spreading to the CSF may occur during treatment with DMF.

Oxygenation and adenosine deaminase support growth and proliferation of ex vivo cultured Drosophila wing imaginal discs.

The Drosophila wing imaginal disc has been an important model system over past decades for discovering novel biology related to development, signaling and epithelial morphogenesis. Novel experimental approaches have been enabled using a culture setup that allows ex vivo cultures of wing discs. Current setups, however, are not able to sustain both growth and cell-cycle progression of wing discs ex vivo We discover here a setup that requires both oxygenation of the tissue and adenosine deaminase activity in the medium, and supports both growth and proliferation of wing discs for 9 h. Nonetheless, further work will be required to extend the duration of the culturing and to enable live imaging of the cultured discs in the future.

THADA Regulates the Organismal Balance between Energy Storage and Heat Production.

Human susceptibility to obesity is mainly genetic, yet the underlying evolutionary drivers causing variation from person to person are not clear. One theory rationalizes that populations that have adapted to warmer climates have reduced their metabolic rates, thereby increasing their propensity to store energy. We uncover here the function of a gene that supports this theory. THADA is one of the genes most strongly selected during evolution as humans settled in different climates. We report here that THADA knockout flies are obese, hyperphagic, have reduced energy production, and are sensitive to the cold. THADA binds the sarco/ER Ca2+ ATPase (SERCA) and acts on it as an uncoupler. Reducing SERCA activity in THADA mutant flies rescues their obesity, pinpointing SERCA as a key effector of THADA function. In sum, this identifies THADA as a regulator of the balance between energy consumption and energy storage, which was selected during human evolution.

Recurrent trimethoprim-sulfamethoxazole-induced aseptic meningitis with associated ampicillin-induced myoclonic twitches
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OBJECTIVE: To report a case of recurrent trimethoprim-sulfamethoxazole-induced aseptic meningitis with associated ampicillin-induced myoclonic twitches. MATERIALS AND METHODS: The patient was investigated using cerebral computed tomography, magnetic resonance imaging, cerebrospinal fluid examination, and electroencephalography. Written informed consent was obtained from the patient for access to clinical files for research purposes and publication. RESULTS: We present a middle-aged woman with two recurrent episodes of aseptic meningitis after treatment with trimethoprim-sulfamethoxazole. Additionally, she developed myoclonic twitches as a rare side effect of ampicillin. CONCLUSION: Aseptic meningitis is a rare adverse reaction to medications like antibiotics. The pathogenesis of trimethoprim-sulfamethoxazole-induced aseptic meningitis is not yet completely understood, but an immune-mediated hypersensitivity reaction is suspected. If patients with an antibiotic therapy due to a systemic or local infection present with severe headache, not only common diagnosis of a parainfectious headache, but also antibiotic-induced aseptic meningitis should be considered.
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Protocols to Study Growth and Metabolism in Drosophila.

Signaling pathways such as the insulin/insulin-like growth factor pathway concurrently regulate organismal growth and metabolism. Drosophila has become a popular model system for studying both organismal growth and metabolic regulation. Care must be taken, however, when assessing such phenotypes because they are quantitative in nature, and influenced by environment. This chapter first describes how to control animal age and nutrient availability, since growth and metabolism are sensitive to these parameters. It then provides protocols for measuring tissue growth, cell size, and metabolic parameters such as stored lipids and glycogen, and circulating sugars.

PPP2R5C Couples Hepatic Glucose and Lipid Homeostasis.

In mammals, the liver plays a central role in maintaining carbohydrate and lipid homeostasis by acting both as a major source and a major sink of glucose and lipids. In particular, when dietary carbohydrates are in excess, the liver converts them to lipids via de novo lipogenesis. The molecular checkpoints regulating the balance between carbohydrate and lipid homeostasis, however, are not fully understood. Here we identify PPP2R5C, a regulatory subunit of PP2A, as a novel modulator of liver metabolism in postprandial physiology. Inactivation of PPP2R5C in isolated hepatocytes leads to increased glucose uptake and increased de novo lipogenesis. These phenotypes are reiterated in vivo, where hepatocyte specific PPP2R5C knockdown yields mice with improved systemic glucose tolerance and insulin sensitivity, but elevated circulating triglyceride levels. We show that modulation of PPP2R5C levels leads to alterations in AMPK and SREBP-1 activity. We find that hepatic levels of PPP2R5C are elevated in human diabetic patients, and correlate with obesity and insulin resistance in these subjects. In sum, our data suggest that hepatic PPP2R5C represents an important factor in the functional wiring of energy metabolism and the maintenance of a metabolically healthy state.

DENR-MCT-1 promotes translation re-initiation downstream of uORFs to control tissue growth.

During cap-dependent eukaryotic translation initiation, ribosomes scan messenger RNA from the 5' end to the first AUG start codon with favourable sequence context. For many mRNAs this AUG belongs to a short upstream open reading frame (uORF), and translation of the main downstream ORF requires re-initiation, an incompletely understood process. Re-initiation is thought to involve the same factors as standard initiation. It is unknown whether any factors specifically affect translation re-initiation without affecting standard cap-dependent translation. Here we uncover the non-canonical initiation factors density regulated protein (DENR) and multiple copies in T-cell lymphoma-1 (MCT-1; also called MCTS1 in humans) as the first selective regulators of eukaryotic re-initiation. mRNAs containing upstream ORFs with strong Kozak sequences selectively require DENR-MCT-1 for their proper translation, yielding a novel class of mRNAs that can be co-regulated and that is enriched for regulatory proteins such as oncogenic kinases. Collectively, our data reveal that cells have a previously unappreciated translational control system with a key role in supporting proliferation and tissue growth.

Insulin/IGF signaling drives cell proliferation in part via Yorkie/YAP.

The insulin/IGF signaling (IIS) pathway is a potent inducer of cell proliferation in normal development and in cancer. The mechanism by which this occurs, however, is not completely understood. The Hippo signaling pathway regulates cell proliferation via the transcriptional co-activator Yorkie/YAP, however the signaling inputs regulating Hippo activity are not fully elucidated. Here we present evidence linking these two conserved, oncogenic pathways in Drosophila and in mammalian cells. We find that activation of IIS and of Yorkie signaling correlate positively in hepatocellular carcinoma. We show that IIS activates Yorkie in vivo, and that Yorkie plays an important role in the ability of IIS to drive cell proliferation. Interestingly, we also find the converse--that Yorkie signaling activates components of the insulin/TOR pathway. In sum, this crosstalk between IIS and Yorkie leads to coordinated regulation of these two oncogenic pathways.

Depression in patients with Huntington disease correlates with alterations of the brain stem raphe depicted by transcranial sonography.

BACKGROUND: Transcranial sonography (TCS) has become a new diagnostic tool in the evaluation of extrapyramidal disorders. Studies of TCS report alterations of the mesencephalic raphe in patients with depression. The aim of this study was to evaluate TCS findings in patients with Huntington disease in correlation with their neurologic and psychiatric status. METHODS: We recruited patients with genetically confirmed Huntington disease. The neurological and psychiatric status of participants was assessed by independent physicians. Echogenicities were investigated according to examination protocol for extrapyramidal disorders using a Siemens Sonoline Elegra system. The sonography examiner was blinded for clinical data. RESULTS: We included 39 patients in our study; 21 patients (53.8%) showed symptoms of depression at the time of evaluation and, of those, 15 (71.4%) had hypoechogenic raphe structures. Thirty patients (76.9%) had a history of depressive episodes, 19 (63.3%) of them with hypoechogenic raphe structures. All 9 patients without a history of depressive episodes showed normal echogenicity of raphe structures (sensitivity 63.3%, specificity 100%). Twelve (70.6%) of the 17 patients with Huntington disease who showed psychiatric disturbances prior to the occurrence of motor symptoms exhibited pathological raphe echogenicity (sensitivity 70.6%, specificity 68.2%). LIMITATIONS: Most of the patients were taking antichoreatic medication, which particularly influences neurologic status. Thus, a meaningful interpretation of the correlation between TCS findings and neurologic features was limited. CONCLUSION: As a novel finding, a relation between mesencephalic raphe echogenicity and depressive state could be identified in patients with Huntington disease. An alteration of the serotonergic brain stem raphe might be involved in the pathogenesis of depression in these patients.