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Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective death of motor neurons (MNs), probably by a combination of cell‐ and non‐cell-autonomous processes. The past decades have brought many important insights into the role of astrocytes in nervous system function and disease, including the implication in ALS pathogenesis possibly through the impairment of Ca2+‐dependent astrocyte‐MN cross‐talk. In this respect, it has been recently proposed that altered astrocytic store‐operated Ca2+ entry (SOCE) may underlie aberrant gliotransmitter release and astrocyte‐mediated neurotoxicity in ALS. These observations prompted us to a thorough investigation of SOCE in primary astrocytes from the spinal cord of the SOD1(G93A) ALS mouse model in comparison with the SOD1(WT)‐expressing controls. To this purpose, we employed, for the first time in the field, genetically‐encoded Ca2+ indicators, allowing the direct assessment of Ca2+ fluctuations in different cell domains. We found increased SOCE, associated with decreased expression of the sarco‐endoplasmic reticulum Ca2+‐ATPase and lower ER resting Ca2+ concentration in SOD1(G93A) astrocytes compared to control cells. Such findings add novel insights into the involvement of astrocytes in ALS MN damage.

Obesity is a strong risk factor for cancer progression, posing obesity-related cancer as one of the leading causes of death. Nevertheless, the molecular mechanisms that endow cancer cells with metastatic properties in patients affected by obesity remain unexplored. Here, we show that IL-6 and HGF, secreted by tumor neighboring visceral adipose stromal cells (V-ASCs), expand the metastatic colorectal (CR) cancer cell compartment (CD44v6 +), which in turn secretes neurotrophins such as NGF and NT-3, and recruits adipose stem cells within tumor mass. Visceral adipose-derived factors promote vasculogenesis and the onset of metastatic dissemination by activation of STAT3, which inhibits miR-200a and enhances ZEB2 expression, effectively reprogramming CRC cells into a highly metastatic phenotype. Notably, obesity-associated tumor microenvironment provokes a transition in the transcriptomic expression profile of cells derived from the epithelial consensus molecular subtype (CMS2) CRC patients towards a mesenchymal subtype (CMS4). STAT3 pathway inhibition reduces ZEB2 expression and abrogates the metastatic growth sustained by adipose-released proteins. Together, our data suggest that targeting adipose factors in colorectal cancer patients with obesity may represent a therapeutic strategy for preventing metastatic disease.

Le malattie neurodegenerative sono caratterizzate da disfunzione e perdita di specifiche popolazioni neuronali in risposta ad invecchiamento o eventi tossici o traumatici. Tuttavia, recentemente, è diventato chiaro che la disfunzione astrocitica ha un ruolo importante nei processi degenerativi. Infatti, gli astrociti rappresentano la popolazione cellulare maggiore del Sistema Nervoso Centrale (SNC) e costituiscono l’elemento principale per la sua omeostasi. Alterazioni biochimiche e strutturali degli astrociti durante la neuroinfiammazione rappresentano una risposta fisiologica a danni a carico del SNC per minimizzare e riparare il danno iniziale. Tuttavia, danni cerebrali prolungati forniscono segnali dannosi che possono compromettere le funzioni di astrociti e neuroni e causare neuroinfiammazione cronica. La neuroinfiammazione è un processo caratterizzato da attivazione gliale, che sottende ad un ciclo continuo di eventi infiammatori in cui si ha rilascio di citochine infiammatorie ed altri mediatori neurotossici che causano stress ossidativo e impediscono il ripristino funzionale del parenchima cerebrale. Un altro meccanismo implicato nelle malattie neurodegenerative è rappresentato dalla disfunzione mitocondriale. I mitocondri sono organelli dinamici. In particolare, i processi della dinamica mitocondriale (che coinvolgono cicli alternati di fissione/fusione e il loro trasporto assonale) e della biogenesi sono cruciali per l’omeostasi neuronale e la funzionalità sinaptica. Inoltre, un’alterazione dell’equilibrio tra processi di fissione e fusione può determinare il destino delle cellule neuronali. Queste informazioni supportano l’ipotesi che la disfunzione mitocondriale abbia un ruolo importante nel processo degenerativo, a causa dell’alta richiesta di energia da parte delle cellule neuronali per svolgere le loro funzioni, tra cui neurogenesi e differenziamento neuronale. Ad oggi, la correlazione tra neuroinfiammazione, disfunzione mitocondriale e neurodege, Neurodegenerative disorders are characterized by dysfunction and loss of specific neuronal populations in response to age-related, or toxic and traumatic events. Recently, it has become clear that astrocytic dysfunction plays a relevant role in neurodegenerative processes. In fact, astrocytes represent the main type of glia in the central nervous system (CNS) and constitute the principal element of the brain homeostatic system. Biochemical and structural changes of astrocytes during neuroinflammation represent a physiological response to CNS injury to minimize and repair the initial damage. Nevertheless, prolonged brain insults provide detrimental signals that can compromise astrocytic and neuronal functions and lead to chronic neuroinflammation. In fact, neuroinflammation is characterized by sustained glial activation (reactive astrogliosis) and the generation of an inflammatory loop, through the release of cytokines and other neurotoxic mediators that cause oxidative stress and limit functional repair of brain parenchyma. Another hallmark of neurodegenerative disorders is represented by mitochondrial dysfunction. Mitochondria are very dynamic organelles. In particular, mitochondrial dynamic processes (involving alternation of fission/fusion cycles and their axonal transport) and biogenesis are crucial for neuronal homeostasis and synaptic function. Moreover, alteration of the balance between fission and fusion can determine the fate of neuronal cells. This knowledge supports the hypothesis that alteration of mitochondrial function and metabolism plays an important role in the neurodegenerative process because neuronal cells require high levels of energy to perform their functions, such as during neuronal differentiation. So far, the correlation between neuroinflammation, mitochondrial dysfunction and neurodegeneration has been poorly investigated. In this study, we describe the effects of a number of natural anti-oxidants in rescuing astrocytic function and neuron

Astrocytes have emerged as critical elements for the maintenance and function of the central nervous system. The expression on their cell membrane of RAGE and TLR4 receptors makes astrocytes susceptible to High-mobility group box 1 (HMGB1), a nuclear protein typically released in the extracellular milieu by living cells experiencing physiological stress conditions or by damaged cells. Here, we show that the interaction of HMGB1 with normal spinal cord astrocytes induces the astrocytic production of neurotrophic factors, particularly brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF). Multiple investigations suggest a role for HMGB1 in amyotrophic lateral sclerosis (ALS). Yet, no mechanistic information on the implication of HMGB1 signaling in this disorder is currently available. We demonstrate that non-transgenic and transgenic SOD1WT spinal motor neurons exhibit only a basal nucleus-to-cytoplasm shuttling of the HMGB1 protein. Conversely, in SOD1G93A ALS mouse spinal cords, HMGB1 significantly translocates from the nucleus to the cytoplasm of motor neurons, thereby suggesting that it may be eventually released in the extracellular environment during the progression of the disease. We postulate that extracellular HMGB1 can paracrinally interact with the neighboring astrocytes in an attempt to counteract the neurodegenerative process. Yet, at variance with normal cells, SOD1G93A-expressing astrocytes show impaired capacity to raise BDNF and GDNF levels upon HMGB1 stimulation. Our data suggest that HMGB1 have a potential to promote neuroprotective actions by healthy astrocytes. However, this neurotrophic response is disrupted in ALS astrocytes. This indicates that diseased astroglial cells may exacerbate motor neuron degeneration in ALS because of the loss of their neurosupportive functions.

Nel seguente lavoro verrà illustrato e discusso un caso clinico che, per le sue specificità, risulta particolarmente attinente al tema congressuale: il tema del corpo quale ‘luogo’ del conflitto tra cultura tradizionale e modernità, psicopatologia e credenze, collettivo ed individuale, intrapsichico e relazionale. Si tratta della storia di un paziente nigeriano, il quale nel corso di pochi mesi assiste alla morte, misteriosa ed improvvisa, dei suoi due fratelli. A questa seguirà, in simili circostanze, quella della madre e della zia, mentre Edward cadrà in coma per due settimane e svilupperà poi una sintomatologia di carattere dissociativo e psicotico, dalla quale si “salverà” soltanto fuggendo in Occidente. Nel corso della terapia, Edward porta il proprio modello esplicativo, centrato sulle conseguenze del rifiuto dei fratelli di raccogliere l’eredità rituale del padre dopo la sua morte, assumendone il ruolo di guaritore tradizionale/stregone che quest’ultimo aveva nel proprio villaggio, e sulla stregoneria come dispositivo responsabile delle morti ‘misteriose’ dei suoi familiari. A partire da una breve illustrazione del caso, verrà proposta un’analisi secondo molteplici, ma complementari, chiavi di lettura: tale, infatti, deve necessariamente essere l’approccio alla storia di questo paziente. Da un lato vi è la necessità di avvicinare questa storia dal punto di vista antropologico-culturale, analizzando il ruolo di stregoneria, religione e di alcune variabili di tipo storico, sociale e culturale nella comprensione della sofferenza soggettiva e delle vicende occorse al paziente. Dall’altro sarà sottolineata la necessità di pensare alla diagnosi integrando gli aspetti di psicopatologia dinamica con gli aspetti culturali. Sarà successivamente considerata l’ipotesi traumatica, che potrebbe a sua volta spiegare molti aspetti sintomatologici osservati facendo riferimenti all’ipotesi della dissociazione strutturale della personalità. Infine, viene avviata

Aims: Mitochondria are very dynamic organelles. Mitochondrial dynamics (alternation of fission/fusion cycles and their axonal transport) and biogenesis are crucial for neuronal homeostasis and synaptic function; moreover, alteration of the balance between fission and fusion can determine the fate of neuronal cells. Fission processes require the intervention of Fis1 and the active form of Drp1, whereas fusion is primarily regulated by Opa1 and Mfn1/2. We here focused on correlation between oxidative stress and mitochondrial dynamics and biogenesis. Materials and Methods: We compared the effect of hydrogen peroxide and Rotenone (a neurotoxin that inhibits the Complex-I of electrons transport chain), on primary cortical neurons or models of neurodegeneration based on neuroblastoma or PC12 cells. Protein levels and distribution (cytoplasm, mitochondria or nuclei) were assessed by western blots and immunofluorescence imaging. Results: Exposure of neurons or neuroblastoma to Rotenone determined a dose-dependent (200-400-800 nM) decrease of P-Drp1 and a biphasic trend of Opa1 and Mfn2 in a time-dependent manner (1-3-6-24h). In PC12 cells, alterations of mitochondrial proteins in response to hydrogen peroxide was paralleled by differential distribution (cytoplasm/nuclei) of oxidative-stress sensors (DJ-1, Nrf2) and proteins regulating mitochondrial biogenesis (mtTFAM and PGC1a), while determining a dose- and time-dependent increase of ROS and ATP depletion. Interestingly, human fibroblasts showed similar changes in response to rotenone but a different trend in response to Amyloid-beta oligomers. Discussion/Conclusions: These studies suggest 1) the existence of a complex cross-talk underlying mitochondrial dynamics and biogenesis, 2) alteration of mitochondrial dynamic proteins as biomarkers of mitochondrial dysfunction in neurodegenerative processes.

Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia-neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS. © 2013 Springer Basel

Growing evidence indicates that astrocytes cannot be just considered as passive supportive cells deputed to preserve neuronal activity and survival, but rather they are involved in a striking number of active functions that are critical to the performance of the central nervous system (CNS). As a consequence, it is becoming more and more evident that the peculiar properties of these cells can actively contribute to the extraordinary functional complexity of the brain and spinal cord. This new perception of the functioning of the CNS opens up a wide range of new possibilities to interpret various physiological and pathological events, and moves the focus beyond the neuronal compartment toward astrocyte-neuron interactions. With this in mind, here we provide a synopsis of the activities astrocytes perform in normal conditions, and we try to discuss what goes wrong with these cells in specific pathological conditions, such as Alzheimer disease, prion diseases and amyotrophic lateral sclerosis. © 2012 Landes Bioscience. Do not distribute

Collective evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is non-cell-autonomous and requires the interaction with the neighboring astrocytes. Recently, we reported that a subpopulation of spinal cord astrocytes degenerates in the microenvironment of motor neurons in the hSOD1 G93A mouse model of ALS. Mechanistic studies in vitro identified a role for the excitatory amino acid glutamate in the gliodegenerative process via the activation of its inositol 1,4,5-triphosphate (IP 3)-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP 3 can prompt IP 3 receptor (IP 3R)-mediated Ca 2+ release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca 2+ signaling that occurs downstream of mGluR5 in hSOD1 G93A-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca 2+ concentrations ([Ca 2+] i) in the absence of spontaneous oscillations. The interaction of IP 3Rs with the anti-apoptotic protein Bcl-X L was previously described to prevent cell death by modulating intracellular Ca 2+ signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-X L, fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca 2+ oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1 G93A mice with the TAT-BH4 peptide reduces focal degeneration of astrocytes, slightly delays the onset of the disease and improves both motor performance and animal lifespan. Our results point at TAT-BH4 as a novel glioprotective agent with a therapeutic potential for ALS. © The Author 2011. Published by Oxford University Press. All rights reserved