Motor Neurodegenerative Disease Research Articles

Spinal V1 inhibitory interneuron clades differ in birthdate, projections to motoneurons, and heterogeneity.

The complexity of spinal interneuron diversity and circuit organization represents a challenge to understand neural control of movement in normal adults as well as during motor development and in disease. Inhibitory interneurons are a core element of these spinal circuits. V1 interneurons comprise the largest group of inhibitory interneurons in the ventral horn, and their organization remains unclear. Here we present a comprehensive examination of V1 subtypes according to neurogenesis, placement in spinal motor circuits, and motoneuron synaptic targeting. V1 diversity increases during evolution from axial-swimming fishes to limb-based mammalian terrestrial locomotion. This increased diversity is reflected in the size and heterogeneity of the Foxp2-V1 clade, a group closely associated with limb motor pools. We show that Foxp2-V1 interneurons establish the densest direct inhibitory input to motoneurons, especially on cell bodies. These findings are particularly significant because recent studies have shown that motor neurodegenerative diseases like amyotrophic lateral sclerosis (ALS) affect inhibitory V1 synapses on motoneuron cell bodies and Foxp2-V1 interneurons themselves in the earliest stages of pathology.

Metabolomic profiling reveals altered phenylalanine metabolism in Parkinson's disease in an Egyptian cohort.

Introduction: Parkinson's disease (PD) is the most common motor neurodegenerative disease worldwide. Given the complexity of PD etiology and the different metabolic derangements correlated to the disease, metabolomics profiling of patients is a helpful tool to identify patho-mechanistic pathways for the disease development. Dopamine metabolism has been the target of several previous studies, of which some have reported lower phenylalanine and tyrosine levels in PD patients compared to controls. Methods: In this study, we have collected plasma from 27 PD patients, 18 reference controls, and 8 high-risk controls to perform a metabolomic study using liquid chromatography-electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). Results: Our findings revealed higher intensities of trans-cinnamate, a phenylalanine metabolite, in patients compared to reference controls. Thus, we hypothesize that phenylalanine metabolism has been shifted to produce trans-cinnamate via L-phenylalanine ammonia lyase (PAL), instead of producing tyrosine, a dopamine precursor, via phenylalanine hydroxylase (PAH). Discussion: Given that these metabolites are precursors to several other metabolic pathways, the intensities of many metabolites such as dopamine, norepinephrine, and 3-hydroxyanthranilic acid, which connects phenylalanine metabolism to that of tryptophan, have been altered. Consequently, and in respect to Metabolic Control Analysis (MCA) theory, the levels of tryptophan metabolites have also been altered. Some of these metabolites are tryptamine, melatonin, and nicotinamide. Thus, we assume that these alterations could contribute to the dopaminergic, adrenergic, and serotonergic neurodegeneration that happen in the disease.

Insights on the Multifaceted Roles of Wild-Type and Mutated Superoxide Dismutase 1 in Amyotrophic Lateral Sclerosis Pathogenesis.

Amyotrophic Lateral Sclerosis (ALS) is a progressive motor neurodegenerative disease. Cell damage in ALS is the result of many different, largely unknown, pathogenetic mechanisms. Astrocytes and microglial cells play a critical role also for their ability to enhance a deranged inflammatory response. Excitotoxicity, due to excessive glutamate levels and increased intracellular Ca2+ concentration, has also been proposed to play a key role in ALS pathogenesis/progression. Reactive Oxygen Species (ROS) behave as key second messengers for multiple receptor/ligand interactions. ROS-dependent regulatory networks are usually mediated by peroxides. Superoxide Dismutase 1 (SOD1) physiologically mediates intracellular peroxide generation. About 10% of ALS subjects show a familial disease associated with different gain-of-function SOD1 mutations. The occurrence of sporadic ALS, not clearly associated with SOD1 defects, has been also described. SOD1-dependent pathways have been involved in neuron functional network as well as in immune-response regulation. Both, neuron depolarization and antigen-dependent T-cell activation mediate SOD1 exocytosis, inducing increased interaction of the enzyme with a complex molecular network involved in the regulation of neuron functional activity and immune response. Here, alteration of SOD1-dependent pathways mediating increased intracellular Ca2+ levels, altered mitochondria functions and defective inflammatory process regulation have been proposed to be relevant for ALS pathogenesis/progression.

The Efficiency of Direct Maturation: the Comparison of Two hiPSC Differentiation Approaches into Motor Neurons.

Motor neurons (MNs) derived from human-induced pluripotent stem cells (hiPSC) hold great potential for the treatment of various motor neurodegenerative diseases as transplantations with a low-risk of rejection are made possible. There are many hiPSC differentiation protocols that pursue to imitate the multistep process of motor neurogenesis in vivo. However, these often apply viral vectors, feeder cells, or antibiotics to generate hiPSC and MNs, limiting their translational potential. In this study, a virus-, feeder-, and antibiotic-free method was used for reprogramming hiPSC, which were maintained in culture medium produced under clinical good manufacturing practice. Differentiation into MNs was performed with standardized, chemically defined, and antibiotic-free culture media. The identity of hiPSC, neuronal progenitors, and mature MNs was continuously verified by the detection of specific markers at the genetic and protein level via qRT-PCR, flow cytometry, Western Blot, and immunofluorescence. MNX1- and ChAT-positive motoneuronal progenitor cells were formed after neural induction via dual-SMAD inhibition and expansion. For maturation, an approach aiming to directly mature these progenitors was compared to an approach that included an additional differentiation step for further specification. Although both approaches generated mature MNs expressing characteristic postmitotic markers, the direct maturation approach appeared to be more efficient. These results provide new insights into the suitability of two standardized differentiation approaches for generating mature MNs, which might pave the way for future clinical applications.

Cognitive and behavioural but not motor impairment increases brain age in amyotrophic lateral sclerosis.

Age is the most important single risk factor of sporadic amyotrophic lateral sclerosis. Neuroimaging together with machine-learning algorithms allows estimating individuals’ brain age. Deviations from normal brain-ageing trajectories (so called predicted brain age difference) were reported for a number of neuropsychiatric disorders. While all of them showed increased predicted brain-age difference, there is surprisingly few data yet on it in motor neurodegenerative diseases. In this observational study, we made use of previously trained algorithms of 3377 healthy individuals and derived predicted brain age differences from volumetric MRI scans of 112 amyotrophic lateral sclerosis patients and 70 healthy controls. We correlated predicted brain age difference scores with voxel-based morphometry data and multiple different motoric disease characteristics as well as cognitive/behavioural changes categorized according to Strong and Rascovsky. Against our primary hypothesis, there was no higher predicted brain-age difference in the amyotrophic lateral sclerosis patients as a group. None of the motoric phenotypes/characteristics influenced predicted brain-age difference. However, cognitive/behavioural impairment led to significantly increased predicted brain-age difference, while slowly progressive as well as cognitive/behavioural normal amyotrophic lateral sclerosis patients had even younger brain ages than healthy controls. Of note, the cognitive/behavioural normal amyotrophic lateral sclerosis patients were identified to have increased cerebellar brain volume as potential resilience factor. Younger brain age was associated with longer survival. Our results raise the question whether younger brain age in amyotrophic lateral sclerosis with only motor impairment provides a cerebral reserve against cognitive and/or behavioural impairment and faster disease progression. This new conclusion needs to be tested in subsequent samples. In addition, it will be interesting to test whether a potential effect of cerebral reserve is specific for amyotrophic lateral sclerosis or can also be found in other neurodegenerative diseases with primary motor impairment.

COVID-19 and Parkinson's Disease: Possible Links in Pathology and Therapeutics.

The outbreak of SARs-CoV-2 with emerging new variants is leading to global health crisis and has brought a major concern for patients with comorbidities. Parkinson's disease (PD) is a motor neurodegenerative disease involving various metabolic and psychological ailments along with the common occurrence of hyposmia as observed in COVID-19 patients. In addition, the observed surplus inflammatory responses in both diseases are also alarming. Alongside, angiotensin-converting enzyme 2 (ACE2) receptor, essentially required by SARS-CoV-2 to enter the cell and dopamine decarboxylase (DDC), required for dopamine synthesis is known to co-regulate in thenon-neuronal cells. Taken together, these conditions suggested the probable reciprocal pathological relation between COVID-19 and PD and also suggested that during comorbidities, the disease diagnosis and therapeutics are critical and may engender severe health complications. In this review, we discuss various events and mechanisms which may have implications for the exacerbation of PD conditions and must be taken into account during the treatment of patients.

Implications of intracellular protein degradation pathways in Parkinson's disease and therapeutics.

Parkinson's disease (PD) pathology is the most common motor neurodegenerative disease that occurs due to the progressive degeneration of dopaminergic neurons of the nigrostriatal pathway of the brain. The histopathological hallmark of the disease is fibrillary aggregate called Lewy bodies which majorly contain α-synuclein, suggesting the critical implication of diminished protein degradation mechanisms in disease pathogenesis. This α-synuclein-containing Lewy bodies are evident in both experimental models as well as in postmortem PD brain and are speculated to be pathogenic but still, the lineal association between these aggregates and the complexity of disease pathology is not yet well established and needs further attention. However, it has been reported that α-synuclein aggregates have consorted with the declined proteasome and lysosome activities. Therefore, in this review, we reappraise intracellular protein degradation mechanisms during PD pathology. This article focused on the findings of the last two decades suggesting the implications of protein degradation mechanisms in disease pathogenesis and based on shreds of evidence, some of the approaches are also suggested which may be adopted to find out the novel therapeutic targets for the management of PD patients.

Hydrogen Peroxide and Amyotrophic Lateral Sclerosis: From Biochemistry to Pathophysiology.

Free radicals are unstable chemical reactive species produced during Redox dyshomeostasis (RDH) inside living cells and are implicated in the pathogenesis of various neurodegenerative diseases. One of the most complicated and life-threatening motor neurodegenerative diseases (MND) is amyotrophic lateral sclerosis (ALS) because of the poor understanding of its pathophysiology and absence of an effective treatment for its cure. During the last 25 years, researchers around the globe have focused their interest on copper/zinc superoxide dismutase (Cu/Zn SOD, SOD1) protein after the landmark discovery of mutant SOD1 (mSOD1) gene as a risk factor for ALS. Substantial evidence suggests that toxic gain of function due to redox disturbance caused by reactive oxygen species (ROS) changes the biophysical properties of native SOD1 protein thus, instigating its fibrillization and misfolding. These abnormal misfolding aggregates or inclusions of SOD1 play a role in the pathogenesis of both forms of ALS, i.e., Sporadic ALS (sALS) and familial ALS (fALS). However, what leads to a decrease in the stability and misfolding of SOD1 is still in question and our scientific knowledge is scarce. A large number of studies have been conducted in this area to explore the biochemical mechanistic pathway of SOD1 aggregation. Several studies, over the past two decades, have shown that the SOD1-catalyzed biochemical reaction product hydrogen peroxide (H2O2) at a pathological concentration act as a substrate to trigger the misfolding trajectories and toxicity of SOD1 in the pathogenesis of ALS. These toxic aggregates of SOD1 also cause aberrant localization of TAR-DNA binding protein 43 (TDP-43), which is characteristic of neuronal cytoplasmic inclusions (NCI) found in ALS. Here in this review, we present the evidence implicating the pivotal role of H2O2 in modulating the toxicity of SOD1 in the pathophysiology of the incurable and highly complex disease ALS. Also, highlighting the role of H2O2 in ALS, we believe will encourage scientists to target pathological concentrations of H2O2 thereby halting the misfolding of SOD1.

Senolytics: A Novel Strategy for Neuroprotection in ALS?

Amyotrophic lateral sclerosis (ALS) is a progressive motor neurodegenerative disease that currently has no cure and has few effective treatments. On a cellular level, ALS manifests through significant changes in the proper function of astrocytes, microglia, motor neurons, and other central nervous system (CNS) cells, leading to excess neuroinflammation and neurodegeneration. Damage to the upper and lower motor neurons results in neural and muscular dysfunction, leading to death most often due to respiratory paralysis. A new therapeutic strategy is targeting glial cells affected by senescence, which contribute to motor neuron degeneration. Whilst this new therapeutic approach holds much promise, it is yet to be trialled in ALS-relevant preclinical models and needs to be designed carefully to ensure selectivity. This review summarizes the pathways involved in ALS-related senescence, as well as known senolytic agents and their mechanisms of action, all of which may inform strategies for ALS-focused drug discovery efforts.

Neurologists\u2019 current practice and perspectives on communicating the diagnosis of a motor neurodegenerative condition: a UK survey

BackgroundThe communication of a life-changing diagnosis can be a difficult task for doctors with potential long-term effects on patient outcomes. Although several studies have addressed the experiences of individuals with motor neurodegenerative diseases in receiving this diagnosis, a significant research gap exists regarding professionals’ perspectives, especially in the UK. This study aimed to assess UK neurologists’ current practice and perspectives on delivering the diagnosis of a motor neurodegenerative disease, explore different aspects of the process and detail the potential challenges professionals might face.MethodsWe conducted an anonymised online survey with 44 questions, grouped into four sections; basic demographic information, current practice, the experience of breaking bad news and education and training needs.ResultsForty-nine professionals completed the survey. Overall, participants seemed to meet the setting-related standards of good practice; however, they also acknowledged the difficulty of this aspect of their clinical work, with about half of participants (46.5%) reporting moderate levels of stress while breaking bad news. Patients’ relatives were not always included in diagnostic consultations and participants were more reluctant to promote a sense of optimism to patients with poorer prognosis. Although professionals reported spending a mean of around 30–40 min for the communication of these diagnoses, a significant proportion of participants (21–39%) reported significantly shorter consultation times, highlighting organisational issues related to lack of capacity. Finally, the majority of participants (75.5%) reported not following any specific guidelines or protocols but indicated their interest in receiving further training in breaking bad news (78.5%).ConclusionsThis was the first UK survey to address neurologists’ practice and experiences in communicating these diagnoses. Although meeting basic standards of good practice was reported by most professionals, we identified several areas of improvement. These included spending enough time to deliver the diagnosis appropriately, including patients’ relatives as a standard, promoting a sense of hope and responding to professionals’ training needs regarding breaking bad news.

Anosognosia in amyotrophic lateral sclerosis: A cross-sectional study of 85 individuals and their relatives.

Amyotrophic lateral sclerosis (ALS) has long been considered a pure motor neurodegenerative disease. However, now, extra-motor manifestations such as cognitive-behavioral disorders are considered not rare and are even a severity factor of the disease. Experiencing anosognosia (i.e., the inability to recognize neurological symptoms) might affect care and treatment compliance in ALS. Regardless, this pivotal feature has been little investigated. By comparing patients' and caregivers' reports, we analysed whether patients with ALS would experience a lack of awareness about their executive disorders and their apathy symptoms. From the ALS reference center in Paris, we included 85 patients (47 men, mean [SD] age 60.5 [12] years and ALS-Functional Rating Scale-revised score 8 to 46) and their primary family caregivers who all completed the Dysexecutive Questionnaire (DEX) and the Apathy Evaluation Scale (AES). Overall scores and answers were compared by agreement/disagreement statistical methods. Caregivers reported higher levels of cognitive-behavioral disorders than did patients, but reports matched when cognitive-behavioral disorders were absent or mild. With published DEX and AES cutoffs, 32% and 51% of patients had executive disorders and apathy, respectively. In these patients with significant impairment, Bland-Altman plots (i.e., visual display agreement that represents the difference between the patient's and caregiver's scores as a function of their average) showed a strong discrepancy between joint reports: patients underestimated their symptoms by a mean bias of -6.81 DEX points (95% confidence interval -11.88, -1.75) and -8.85 AES points (95% confidence interval -11.72, -5.98). We found no clear relationship between bulbar or spinal ALS subtypes and anosognosia. ALS patients with a cognitive-behavioral phenotype show anosognosia by a mismatch between self and proxy reports, which warrants further investigation in neuroimaging. Systematic longitudinal screening of anosognosia is needed to propose targeted psychoeducation in patient-caregiver dyads showing disagreement.

Rehabilitative Impact of Exercise Training on Human Skeletal Muscle Transcriptional Programs in Parkinson's Disease.

Parkinson’s disease (PD) is the most common motor neurodegenerative disease, and neuromuscular function deficits associated with PD contribute to disability. Targeting these symptoms, our laboratory has previously evaluated 16-week high-intensity resistance exercise as rehabilitative training (RT) in individuals with PD. We reported significant improvements in muscle mass, neuromuscular function (strength, power, and motor unit activation), indices of neuromuscular junction integrity, total and motor scores on the unified Parkinson’s disease rating scale (UPDRS), and total and sub-scores on the 39-item PD Quality of Life Questionnaire (PDQ-39), supporting the use of RT to reverse symptoms. Our objective was to identify transcriptional networks that may contribute to RT-induced neuromuscular remodeling in PD. We generated transcriptome-wide skeletal muscle RNA-sequencing in 5 participants with PD [4M/1F, 67 ± 2 years, Hoehn and Yahr stages 2 (n = 3) and 3 (n = 2)] before and after 16-week high intensity RT to identify transcriptional networks that may in part underpin RT-induced neuromuscular remodeling in PD. Following RT, 304 genes were significantly upregulated, notably related to remodeling and nervous system/muscle development. Additionally, 402 genes, primarily negative regulators of muscle adaptation, were downregulated. We applied the recently developed Pathway-Level Information ExtractoR (PLIER) method to reveal coordinated gene programs (as latent variables, LVs) that differed in skeletal muscle among young (YA) and old (OA) healthy adults and PD (n = 12 per cohort) at baseline and in PD pre- vs. post-RT. Notably, one LV associated with angiogenesis, axon guidance, and muscle remodeling was significantly lower in PD than YA at baseline and was significantly increased by exercise. A different LV annotated to denervation, autophagy, and apoptosis was increased in both PD and OA relative to YA and was also reduced by 16-week RT in PD. Thus, this analysis identified two novel skeletal muscle transcriptional programs that are dysregulated by PD and aging, respectively. Notably, RT has a normalizing effect on both programs in individuals with PD. These results identify potential molecular transducers of the RT-induced improvements in neuromuscular remodeling and motor function that may aid in optimizing exercise rehabilitation strategies for individuals with PD.

The Small-Molecule Flunarizine in Spinal Muscular Atrophy Patient Fibroblasts Impacts on the Gemin Components of the SMN Complex and TDP43, an RNA-Binding Protein Relevant to Motor Neuron Diseases.

The motor neurodegenerative disease spinal muscular atrophy (SMA) is caused by alterations of the survival motor neuron 1 (SMN1) gene involved in RNA metabolism. Although the disease mechanisms are not completely elucidated, SMN protein deficiency leads to abnormal small nuclear ribonucleoproteins (snRNPs) assembly responsible for widespread splicing defects. SMN protein localizes in nuclear bodies that are lost in SMA and adult onset amyotrophic lateral sclerosis (ALS) patient cells harboring TDP-43 or FUS/TLS mutations. We previously reported that flunarizine recruits SMN into nuclear bodies and improves the phenotype of an SMA mouse model. However, the precise mode of action remains elusive. Here, a marked reduction of the integral components of the SMN complex is observed in severe SMA patient fibroblast cells. We show that flunarizine increases the protein levels of a subset of components of the SMN-Gemins complex, Gemins2-4, and markedly reduces the RNA and protein levels of the pro-oxydant thioredoxin-interacting protein (TXNIP) encoded by an mRNA target of Gemin5. We further show that SMN deficiency causes a dissociation of the localization of the SMN complex components from the same nuclear bodies. The accumulation of TDP-43 in SMN-positive nuclear bodies is also perturbed in SMA cells. Notably, TDP-43 is found to co-localize with SMN in nuclear bodies of flunarizine-treated SMA cells. Our findings indicate that flunarizine reverses cellular changes caused by SMN deficiency in SMA cells and further support the view of a common pathway in RNA metabolism underlying infantile and adult motor neuron diseases.

A Quantitative Study of Empty Baskets in Essential Tremor and Other Motor Neurodegenerative Diseases.

The underlying biology of essential tremor (ET) is poorly understood. Purkinje cell (PC) loss has been observed in some studies, although this finding remains somewhat controversial. Basket cells are interneurons whose axonal collaterals form a plexus around PC soma. When there is PC loss, this basket plexus appears empty. We used dual immunohistochemical staining for calbindin D28k and glutamic acid decarboxylase to quantify "empty baskets" as an indirect and alternative method of detecting PC loss. Microscopic analyses on 127 brains included ET and a spectrum of motor neurodegenerative diseases (50 ET, 27 spinocerebellar ataxias [SCAs], 25 Parkinson disease, 25 controls). The median percentage of empty baskets in ET patients was 1.5 times higher than controls (48.8% vs 33.5%, p < 0.001) but lower in ET than in SCA1 (59.7%, p = 0.011), SCA2 (77.5%, p = 0.003), and SCA6 (87.0%, p < 0.001). PC loss is not a feature of SCA3, and the median percentage of empty baskets (30.1%) was similar to controls (p = 0.303). These data provide support for PC loss in ET and are consistent with the notion that ET could represent a mild form of cerebellar degeneration with an intermediate degree of PC loss.

Application of nanoscale polymer colloid carriers for targeted delivery of the brain-derived neurotrophic factor through the blood-brain barrier in experimental parkinsonism

Parkinson disease is one of the common age-related motor neurodegenerative diseases, in which dopamine neurons degeneration is considered to be pathognomic for the development of motor disfunction. Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, which is considered to be a key regulator of neuronal plasticity. BDNF, being a large molecule, does not pass through the blood-brain barrier (BBB). Synthetic polymer nanoparticles (NP), covered by surfactant, provide the phenomenon of “Trojan hoarse” and enable BDNF to penetrate into the brain tissue. For modelling of parkinsonism we used an intraperitoneal (i.p.) injection of neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) which was injected to the C57BL/6 mice with subsequest treatment with normal saline (group 1), BDNF (group 2), nanoparticulate BDNF (group 3) and surfactant-coated nanoparticulate BDNF (group 4). After 90 min, 24 hours, 72 hours and 7 days manifestations of parkinsonism were evaluated using behavioural tests of open field, rota-rod, assessment of the tremor, length of the body and pace. At the end of experiment the brain was sampled for histological evaluation of changes in the striatum and midbrain and concentration of BDNF in the brain tissues. The results of the experiments demonstrated that nanoparticulate BDNF covered with surfactant significanltly reduced rigidity of the skeletal muscles, oligokinesia and tremor, and also significantly increased BDNF concentration in the brain tissues.

Multiple Kernel Learning Based Classification of Parkinson's Disease With Multi-Modal Transcranial Sonography.

Parkinson's Disease (PD) is the most common motor neurodegenerative disease in elderly population. Transcranial sonography (TCS) has become a popular imaging tool for diagnosis of PD in clinical practice. Moreover, several pioneering work have developed the computer-aided diagnosis (CAD) for PD with the transcranial B-mode sonography (TBS). It is worth noting that TCS not only has the TBS modality, but also can image the blood flow of major cerebral arteries, which is named transcranial Doppler sonography (TDS). TDS also has been applied to evaluate PD patients with orthostatic hypotension. However, the TDS-based CAD for PD has not been investigated. Since TBS and TDS provide the complementary structural and functional information about brain, it is feasible to develop a multi-modal TCS-based CAD for PD by combining both TBS and TDS. Therefore, in this work, we propose a multiple kernel learning (MKL) based CAD for PD with multi-modal TCS imaging. Particularly, the statistical and texture features are extracted from the midbrain region from TBS images, and the features about blood flow are calculated from the spectrum curves in TDS. The multi-modal features are then fed to a MKL classifier for classification of PD. The experimental results show that the multi-modal TCS-based method outperforms both the single-modal TBS- and TDS-based algorithm, which suggests the feasibility and effectiveness of combining TBS and TDS for diagnosis of PD.

Vitamin E deficiency in South Asian population and the therapeutic use of alpha-tocopherol (Vitamin E) for correction of anemia.

Mild to moderate vitamin E deficiency because of inadequate consumption of vitamin E-rich foods and intestinal fat malabsorption is common in growing children, women of reproductive age and elderly South Asian population. Severe vitamin E deficiency may lead to peripheral and motor neurodegenerative diseases (e.g ataxia and motor skeletal myopathy), impaired immune response and free radical-induced hemolytic anemias. Vitamin E insufficiency and/or deficiency status in the general Pakistani population has not been sufficiently investigated. Moreover, there are challenges in determining vitamin E status in apparently healthy humans due to variations in their age, sources of consumed vitamin E and plasma lipid levels. Oxidative stress-induced reactive oxygen species have been shown to cause ineffective erythropoiesis and enhanced lysis of erythrocytes in some of the experimental animals and humans. Several studies on patients with various types of inherited hemolytic anemias, chronic renal disease, premature low birth infants and apparently healthy humans have shown that vitamin E might be therapeutically effective in the prevention and/ or treatment of anemia in these subjects.

Tissue specific expression and in-silico characterization of a putative cysteine synthase gene from Lathyrus sativus L.

Grass pea (Lathyrus sativus L.) is a worldwide popular pulse crop especially for its protein rich seeds with least production cost. However, the use of the crop became controversial due to the presence of non-protein amino acid, β-N-oxalyl-L-α, β-diaminopropionic acid (β-ODAP) in its seed and leaf, which is known as the principle neurotoxin to cause neurolathyrism (a motor neurodegenerative disease of humans and animals) during prolonged consumption as regular diet. Till date, the knowledge on β-ODAP biosynthesis in Lathyrus sp. is limited only to a small part of the complex bio-chemical steps involved including a few known sulfur-containing enzymes (viz. cysteine synthase, ODAP synthase etc.). In Lathyrus sativus, biosynthesis of β-ODAP varies differentially in a tissue-specific manner as well as in response to several environmental stresses viz. zinc deficiency, iron over-exposure, moisture stress etc. In the present study, a novel cysteine synthase gene (LsCSase) from Lathyrus sativus L was identified and characterized through bioinformatics approaches. The bioinformatic analysis revealed that LsCSase showed maximum similarity with the O-acetyl serine (thiol) lyase of Medicago truncatula with respect to several significant sequence-specific conserved motifs (cysK, CBS like, ADH_zinc_N, PALP), sub-cellular localization (chloroplast or cytoplasm) etc., similar to other members of cysteine synthase protein family. Moreover, the tissue-specific regulation of the LsCSase as well as its transcriptional activation under certain previously reported stressed conditions (low Zn+2-high Fe+2, PEG induced osmotic stress) were also documented through quantitative real-time PCR analyses, suggesting a possible link between the LsCSase gene activation and β-ODAP biosynthesis to manage external stresses in grass pea. This preliminary study offers a probable way towards the development of less toxic consumer-safe grass pea by down-regulation or deactivation of such gene/s (cysteine synthase) through genetic manipulations.

Exploring the Interaction of Drosophila TDP-43 and the Type II Voltage-Gated Calcium Channel, Cacophony, in Regulating Motor Function and Behavior.

Amyotrophic lateral sclerosis (ALS) is the most common adult onset motor neurodegenerative disease. The cause of the disease remains obscure, and as such there is no effective treatment or cure. Amyotrophic lateral sclerosis and other neurodegenerative diseases are frequently characterized by dysfunction of the RNA-binding protein, TDP-43. Using model systems to understand the mechanisms underlying TDP-43 dysfunction should accelerate identification of therapeutic targets. A recent report has shown that motor defects caused by the deletion of the Drosophila TDP-43 ortholog, tbph, are not driven by changes in the physiology at the neuromuscular junction. Rather, defective motor burst rhythmicity and coordination, displayed by tbph mutants, are rescued by genetically restoring a voltage-gated calcium channel to either motor neurons or just a single pair of neurons in the brain. If these effects are mirrored in human TDP-43 proteinopathies, these observations could open new avenues to investigate alternative therapeutic targets for these neurodegenerative diseases.

A differential autophagy-dependent response to DNA double-strand breaks in bone marrow mesenchymal stem cells from sporadic ALS patients.

ABSTRACTAmyotrophic lateral sclerosis (ALS) is an incurable motor neurodegenerative disease caused by a diversity of genetic and environmental factors that leads to neuromuscular degeneration and has pathophysiological implications in non-neural systems. Our previous work showed abnormal levels of mRNA expression for biomarker genes in non-neuronal cell samples from ALS patients. The same genes proved to be differentially expressed in the brain, spinal cord and muscle of the SOD1G93A ALS mouse model. These observations support the idea that there is a pathophysiological relevance for the ALS biomarkers discovered in human mesenchymal stem cells (hMSCs) isolated from bone marrow samples of ALS patients (ALS-hMSCs). Here, we demonstrate that ALS-hMSCs are also a useful patient-based model to study intrinsic cell molecular mechanisms of the disease. We investigated the ALS-hMSC response to oxidative DNA damage exerted by neocarzinostatin (NCS)-induced DNA double-strand breaks (DSBs). We found that the ALS-hMSCs responded to this stress differently from cells taken from healthy controls (HC-hMSCs). Interestingly, we found that ALS-hMSC death in response to induction of DSBs was dependent on autophagy, which was initialized by an increase of phosphorylated (p)AMPK, and blocked by the class III phosphoinositide 3-kinase (PI3K) and autophagy inhibitor 3-methyladenine (3MeA). ALS-hMSC death in response to DSBs was not apoptotic as it was caspase independent. This unique ALS-hMSC-specific response to DNA damage emphasizes the possibility that an intrinsic abnormal regulatory mechanism controlling autophagy initiation exists in ALS-patient-derived hMSCs. This mechanism may also be relevant to the most-affected tissues in ALS. Hence, our approach might open avenues for new personalized therapies for ALS.