A multistationary loop model of ALS unveils critical molecular interactions involving mitochondria and glucose metabolism

Amyotrophic lateral sclerosis (ALS) is a poor-prognosis disease with puzzling pathogenesis and inconclusive treatments. We develop a mathematical model of ALS based on a system of interactive feedback loops, focusing on the mutant SOD1G93A mouse. Misfolded mutant SOD1 aggregates in motor neuron (MN) mitochondria and triggers a first loop characterized by oxidative phosphorylation impairment, AMP kinase over-activation, 6-phosphofructo-2-kinase (PFK3) rise, glucose metabolism shift from pentose phosphate pathway (PPP) to glycolysis, cell redox unbalance, and further worsening of mitochondrial dysfunction. Oxidative stress then triggers a second loop, involving the excitotoxic glutamatergic cascade, with cytosolic Ca2+ overload, increase of PFK3 expression, and further metabolic shift from PPP to glycolysis. Finally, cytosolic Ca2+ rise is also detrimental to mitochondria and oxidative phosphorylation, thus closing a third loop. These three loops are overlapped and positive (including an even number of inhibitory steps), hence they form a candidate multistationary (bistable) system. To describe the system dynamics, we model the interactions among the functional agents with differential equations. The system turns out to admit two stable equilibria: the healthy state, with high oxidative phosphorylation and preferential PPP, and the pathological state, with AMP kinase activation, PFK3 over expression, oxidative stress, excitotoxicity and MN degeneration. We demonstrate that the loop system is monotone: all functional agents consistently act toward the healthy or pathological condition, depending on low or high mutant SOD1 input. We also highlight that molecular interactions involving PFK3 are crucial, as their deletion disrupts the system\u2019s bistability leading to a single healthy equilibrium point. Hence, our mathematical model unveils that promising ALS management strategies should be targeted to mechanisms that keep low PFK3 expression and activity within MNs

Abnormal Upregulation of GPR17 Receptor Contributes to Oligodendrocyte Dysfunction in SOD1 G93A Mice

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive loss of motor neurons (MN). Importantly, MN degeneration is intimately linked to oligodendrocyte dysfunction and impaired capacity of oligodendrocyte precursor cells (OPCs) to regenerate the myelin sheath enwrapping and protecting neuronal axons. Thus, improving OPC reparative abilities represents an innovative approach to counteract MN loss. A pivotal regulator of OPC maturation is the P2Y-like G protein-coupled receptor 17 (GPR17), whose role in ALS has never been investigated. In other models of neurodegeneration, an abnormal increase of GPR17 has been invariably associated to myelin defects and its pharmacological manipulation succeeded in restoring endogenous remyelination. Here, we analyzed GPR17 alterations in the SOD1G93A ALS mouse model and assessed in vitro whether this receptor could be targeted to correct oligodendrocyte alterations. Western-blot and immunohistochemical analyses showed that GPR17 protein levels are significantly increased in spinal cord of ALS mice at pre-symptomatic stage; this alteration is exacerbated at late symptomatic phases. Concomitantly, mature oligodendrocytes degenerate and are not successfully replaced. Moreover, OPCs isolated from spinal cord of SOD1G93A mice display defective differentiation compared to control cells, which is rescued by treatment with the GPR17 antagonist montelukast. These data open novel therapeutic perspectives for ALS management

Changes in spine alignment and postural balance after breast cancer surgery: a rehabilitative point of view

Breast cancer is the most common malignant tumor in female patients in developed countries. Recent articles indicate that one-sided mastectomy or minor breast surgery to treat breast cancer can have deleterious effects on posture and the musculoskeletal system. The purpose of this study was to investigate the alterations post-breast cancer surgery of the spine alignment associated to the balance not reported by the noninvasive instrumentation. We enrolled 30 women who had undergone treatment for breast cancer (BG) and were on a waiting-list for rehabilitation treatment and a control group of 30 healthy volunteer women (CG), matched by age and body mass index. The stabilometry was performed using a force platform (Kistler Instruments, Winterthur, Switzerland) test during quiet standing with closed-eyes (EC) and open-eyes (EO), recording the position of the center of pressure (CoP) for 51.2 sec. The stabilogram or the time plot of the two coordinates, X and Y, of the CoP was obtained, which represent anteroposterior and midlateral balance. Spinal posture was measured using the Formetric-4D rasterstereographic system (DIERS, International GmbH, Schlangenbad, Germany), and thoracic kyphotic angle, lumbar lordotic angle, and surface trunk rotation were evaluated. Sixty participants were analyzed (CG:30; BG:30). For the spine rasterstereography a statistically significant difference was shown with regard to anterior-posterior flexion of the trunk major in BG; pelvic inclination and twist of half-pelvis decreased in BG; normalized lumbosacral inversion point decreased in BG; surface rotation major in BG; and lateral deviation major in BG. Compared with the values for the stabilometry test with EO and EC, a statistically significant difference was observed, respectively, for ellipse length (mm; p = 0.04) and ellipse area (mm2; p = 0.04) with EO and in ellipse area (mm2) with EC (p = 0.05), increased in BG for both conditions. No difference was shown for CoP velocity and oscillations between the groups. Breast cancer survivors after prostheses or tissue expanders for mastectomy showed a spine's misalignment present both on the sagittal plane, both on the coronal and frontal plane, increased in BG regard to anterior-posterior flexion of the trunk, surface rotation, and lateral deviation. It is associated with greater energy expenditure for the postural balance control increased in BG with a major ellipse area in EO and EC conditions and major ellipse length in EC condition

The reaching movement in breast cancer survivors. attention to the principles of rehabilitation

Introduction: Breast-cancer is leading cause of morbidity and mortality in women. The prognosis and survival rate of women with breast-cancer have significantly improved worldwide; more attention needs to be paid to rehabilitative interventions after surgery. This paper describes use of reaching movement to assess upper limb motorcontrol and functional ability after breast-cancer surgery (BC). Material and methods: We conducted a cross-sectional observational study consisting of biomechanical evaluation of upper limb limitations in women BC, versus a controlgroup (CG). Thirty breast-cancer survivors and thirty healthy women participated in this study. Both groups were subjected to clinical evaluation of the shoulder joint ROM on the operated side, as an assessment of the muscular-strength of the shoulder with the MRC-scale. The Functional-Assessment was evaluated by the DASH and Constant-Murley-Score. The EORTC QLQ-C30 and VAS were used to measure the quality of life assessment and pain respectively. A Biomechanical evaluation was performed, using Reaching-Task and Surface-EMG. Results: Normal Jerk for BC was higher than CG. Target approaching velocity and movement duration BC was lower than CG. Synergy Anterior Deltoid/Triceps Brachii muscles in CG was higher than BC

Functional and Molecular Changes in the Prefrontal Cortex of the Chronic Mild Stress Rat Model of Depression and Modulation by Acute Ketamine

Stress is a primary risk factor in the onset of neuropsychiatric disorders, including major depressive disorder (MDD). We have previously used the chronic mild stress (CMS) model of depression in male rats to show that CMS induces morphological, functional, and molecular changes in the hippocampus of vulnerable animals, the majority of which were recovered using acute subanesthetic ketamine in just 24 h. Here, we focused our attention on the medial prefrontal cortex (mPFC), a brain area regulating emotional and cognitive functions, and asked whether vulnerability/resilience to CMS and ketamine antidepressant effects were associated with molecular and functional changes in the mPFC of rats. We found that most alterations induced by CMS in the mPFC were selectively observed in stress-vulnerable animals and were rescued by acute subanesthetic ketamine, while others were found only in resilient animals or were induced by ketamine treatment. Importantly, only a few of these modifications were also previously demonstrated in the hippocampus, while most are specific to mPFC. Overall, our results suggest that acute antidepressant ketamine rescues brain-area-specific glutamatergic changes induced by chronic stress

Dopamine-dependent ketamine modulation of glutamatergic synaptic plasticity in the prelimbic cortex of adult rats exposed to acute stress

Traumatic stress is the main environmental risk factor for the development of psychiatric disorders. We have previously shown that acute footshock (FS) stress in male rats induces rapid and long-lasting functional and structural changes in the prefrontal cortex (PFC), which are partly reversed by acute subanesthetic ketamine. Here, we asked if acute FS may also induce any changes in glutamatergic synaptic plasticity in the PFC 24 h after stress exposure and whether ketamine administration 6 h after stress may have any effect. We found that the induction of long-term potentiation (LTP) in PFC slices of both control and FS animals is dependent on dopamine and that dopamine-dependent LTP is reduced by ketamine. We also found selective changes in ionotropic glutamate receptor subunit expression, phosphorylation, and localization at synaptic membranes induced by both acute stress and ketamine. Although more studies are needed to understand the effects of acute stress and ketamine on PFC glutamatergic plasticity, this first report suggests a restoring effect of acute ketamine, supporting the potential benefit of ketamine in limiting the impact of acute traumatic stress