Sub-cellular motor neuron analysis in a model of spinal muscle atrophy

Spinal muscular atrophy (SMA) is a neurogenetic autosomal recessive disorder characterized by degeneration of lower motor neurons associated with muscle atrophy and paralysis. The disease course including onset and severity depends by reduced amounts of the survival motor neuron (SMN) protein. Such a protein is increased when the enzyme glycogen synthase kinase-3beta (GSK3beta) is inhibited. In the present study we used a knockout double transgenic mouse (Smn−/−; SMN1A2G; SMN2) modelling SMAIII to dissect the spinal cord pathology at ultrastructural analysis at prolonged survival time (18 months). We analysed the subcellular structure of spinal cord motor neurons both in baseline conditions and following the administration of a GSK3beta inhibitor. We found that motor neurons increased their diameter confirming our previous light microscopy data. The amount of immunogold labelled SMN particles was dramatically reduced in the whole cell body incuding nucleus and cytoplasm. Remarkably, at nuclear level we could detect marked reduction of the SMN protein with Cajal-like bodies thus mimicking the human disease. In mice receiving long-term lithium administration the level of the SMN protein were massively increase way more than other SMAIII mice and significantly exceeding the levels counted in controls. When compared with control mice administered long-term lithium SMN levels in SMA III mice were overlapping with healthy animals, at large. The effects of lithium on ultrastructural morphology of motor neurons extended to the preservation of mitochondrial compartment which was slightly affected in motor neurons from SMA III mice. These data confirm the essential role of GSK3beta inhibition in increasing the amount of the SMN protein and provide a novel action for an old drug which increases SMN level exceeding any other compound tested so far in this motor neuron pathology. At the same time the beneficial effects of lithium on mitochondrial morphology are confirmed. As an appendix to the present study we wish to mention the ubiquitous nature of these effects which were replicated in non-motor neuron cell lines. Apart from the significance in cell biology this latter observation provide the basis to analyze the effects of a lithium treatment on affected patients using peripheral or skin-derived cell cultures. This work was supported by an educational grant from CUCC

Geosystemics View of Earthquakes

Earthquakes are the most energetic phenomena in the lithosphere: their study and comprehension are greatly worth doing because of the obvious importance for society. Geosystemics intends to study the Earth system as a whole, looking at the possible couplings among the different geo-layers, i.e., from the earth’s interior to the above atmosphere. It uses specific universal tools to integrate different methods that can be applied to multi-parameter data, often taken on different platforms (e.g., ground,marine or satellite observations). Itsmain objective is to understand the particular phenomenon of interest from a holistic point of view. Central is the use of entropy, together with other physical quantities that will be introduced case by case. In this paper, we will deal with earthquakes, as final part of a long-term chain of processes involving, not only the interaction between different components of the Earth’s interior but also the coupling of the solid earth with the above neutral or ionized atmosphere, and finally culminating with the main rupture along the fault of concern. Particular emphasis will be given to some Italian seismic sequences.Publishedid 4121A. Geomagnetismo e PaleomagnetismoJCR Journa

Precursory worldwide signatures of earthquake occurrences on Swarm satellite data

The study of the preparation phase of large earthquakes is essential to understand the physical processes involved, and potentially useful also to develop a future reliable short-term warning system. Here we analyse electron density and magnetic field data measured by Swarm three-satellite constellation for 4.7 years, to look for possible in-situ ionospheric precursors of large earthquakes to study the interactions between the lithosphere and the above atmosphere and ionosphere, in what is called the Lithosphere-Atmosphere-Ionosphere Coupling (LAIC). We define these anomalies statistically in the whole space-time interval of interest and use a Worldwide Statistical Correlation (WSC) analysis through a superposed epoch approach to study the possible relation with the earthquakes. We find some clear concentrations of electron density and magnetic anomalies from more than two months to some days before the earthquake occurrences. Such anomaly clustering is, in general, statistically significant with respect to homogeneous random simulations, supporting a LAIC during the preparation phase of earthquakes. By investigating different earthquake magnitude ranges, not only do we confirm the well-known Rikitake empirical law between ionospheric anomaly precursor time and earthquake magnitude, but we also give more reliability to the seismic source origin for many of the identified anomalies.Publishedid 202872A. Fisica dell'alta atmosferaJCR Journa

Defects in the acid phosphatase ACPT cause recessive hypoplastic amelogenesis imperfecta

We identified two homozygous missense variants (c.428C>T, p.(T143M) and c.746C>T, p.(P249L)) in ACPT, the gene encoding Acid Phosphatase, Testicular, which segregate with hypoplastic Amelogenesis imperfecta (AI) in two unrelated families. ACPT is reported to play a role in odontoblast differentiation and mineralisation by supplying phosphate during dentine formation. Analysis by computerised tomography and scanning electron microscopy of a primary molar tooth from an individual homozygous for the c.746C>T variant, revealed an enamel layer that was hypoplastic but mineralised with prismatic architecture. These findings implicate variants in ACPT as a cause of early failure of amelogenesis during the secretory phase

Specialist and transitional care provision for amelogenesis imperfecta: a UK-wide survey

Background Amelogenesis imperfecta (AI) can be challenging to manage due to the complexity and variation of presentation. Clear care pathways between general practice, specialist paediatric dentistry and adult services are required.Aim To assess the provision of specialist care and transitional care arrangements for paediatric patients with AI in the UK.Method An online survey was disseminated to members of the British Society of Paediatric Dentistry in January 2020. Descriptive analysis was used to interpret the quantitative and qualitative results.Results In total, 115 clinicians across all four nations participated. Most respondents (54%; n = 66), were based in the hospital dental service. Overall, 29% (n = 33) were consultants and 24% (n = 28) were specialists in paediatric dentistry. The most common patient age group seen was 6-12 years old. No clear AI referral pathway into specialist care was reported by 49% (n = 47). A clear transitional care pathway was deemed not to exist by 77% (n = 72), with 85.9% (n = 73) indicating a need. Qualitative analysis themes included 'unclear care pathways' and 'specialist care access problems'.Conclusion Access to specialist paediatric dental care and transition to adult services is not readily available throughout the UK for AI patients. There is a clear need to establish and improve existing pathways

Cell Clearing Systems Bridging Neuro-Immunity and Synaptic Plasticity

In recent years, functional interconnections emerged between synaptic transmission, inflammatory/immune mediators, and central nervous system (CNS) (patho)-physiology. Such interconnections rose up to a level that involves synaptic plasticity, both concerning its molecular mechanisms and the clinical outcomes related to its behavioral abnormalities. Within this context, synaptic plasticity, apart from being modulated by classic CNS molecules, is strongly affected by the immune system, and vice versa. This is not surprising, given the common molecular pathways that operate at the cross-road between the CNS and immune system. When searching for a common pathway bridging neuro-immune and synaptic dysregulations, the two major cell-clearing cell clearing systems, namely the ubiquitin proteasome system (UPS) and autophagy, take center stage. In fact, just like is happening for the turnover of key proteins involved in neurotransmitter release, antigen processing within both peripheral and CNS-resident antigen presenting cells is carried out by UPS and autophagy. Recent evidence unravelling the functional cross-talk between the cell-clearing pathways challenged the traditional concept of autophagy and UPS as independent systems. In fact, autophagy and UPS are simultaneously affected in a variety of CNS disorders where synaptic and inflammatory/immune alterations concur. In this review, we discuss the role of autophagy and UPS in bridging synaptic plasticity with neuro-immunity, while posing a special emphasis on their interactions, which may be key to defining the role of immunity in synaptic plasticity in health and disease

In search for a gold-standard procedure to count motor neurons in the spinal cord

Counting motor neurons within the spinal cord and brainstem represents a seminal step to comprehend the anatomy and physiology of the final common pathway sourcing from the CNS. Motor neuron loss allows to assess the severity of motor neuron disorders while providing a tool to assess disease modifying effects. Counting motor neurons at first implies gold standard identification methods. In fact, motor neurons may occur within mixed nuclei housing a considerable amount of neurons other than motor neurons. In the present review, we analyse various approaches to count motor neurons emphasizing both the benefits and bias of each protocol. A special emphasis is placed on discussing automated stereology. When automated stereology does not take into account sitespecificity and does not distinguish between heterogeneous neuronal populations, it may confound data making such a procedure a sort of “guide for the perplex”. Thus, if on the one hand automated stereology improves our ability to quantify neuronal populations, it may also hide false positives/negatives in neuronal counts. For instance, classic staining for antigens such as SMI-32, SMN and ChAT, which are routinely considered to be specific for motor neurons, may also occur in other neuronal types of the spinal cord. Even site specificity within Lamina IX may be misleading due to neuronal populations having a size and shape typical of motor neurons. This is the case of spinal border cells, which often surpass the border of Lamina VII and intermingle with motor neurons of Lamina IX. The present article discusses the need to join automated stereology with a dedicated knowledge of each specific neuroanatomical setting