Assessment of the upper motor neuron degeneration by detailed motor homunculus cortex thickness in amyotrophic lateral sclerosis / 西安交通大学学报(医学版)

【Objective】 The involvement of upper motor neuron (UMN) degeneration is crucial to the diagnosis of amyotrophic lateral sclerosis (ALS). This study aimed to determine objective and sensitive UMN degeneration markers for an accurate and early diagnosis. 【Methods】 A total of 108 ALS patients and 90 age- and gender-matched control subjects were recruited from ALS Clinic of The First Affiliated Hospital of Xi’an Jiaotong University. The motor homunculus cortex thickness data in MRI were collected from all the participants. The clinical characteristics and UMN clinical examination of bulbar, cervical, thoracic and lumbosacral regions were collected from the ALS patients. 【Results】 Cortical thickness was significantly thinner in the ALS group than in the control group in bilateral head-face-bulbar and upper-limb areas (P<0.05). The cortical thickness of the global UMN positive group was significantly thinner than that of control groups in bilateral head-face-bulbar and upper-limb areas (P<0.05). The cortical thickness of the UMN positive group in the corresponding region was significantly thinner than that of control groups in bilateral head-face-bulbar and upper-limb areas (P<0.05). 【Conclusion】 The thinning of the motor homunculus cortex can be used as an objective marker of UMN involvement in ALS patients in clinical practice.

Neuroimaging advances in patients with amyotrophic lateral sclerosis / 西安交通大学学报(医学版)

Amyotrophic lateral sclerosis (ALS) is a multi-system neurodegenerative disease characterized with degeneration of both motor and non-motor areas. Complicated clinical manifestations and lack of objective biomarkers for upper motor neuron deficits challenged the early diagnosis of ALS. Meanwhile, heterogeneous non-motor symptoms and conflicted treatment effects exacerbated the management and therapy of the disease. The multiparametric functional MRI has the potential to address all the needs for diagnosis, management, and disease modified therapy in ALS. The present paper summarizes the research progress in both motor and non-motor impairment in ALS, as well as their potential value in visualizing disease stages and drug effect evaluation. Focusing on the heterogeneity of the disease and combining with brain and spinal cord imaging may provide direct evidence for disease diagnosis and treatment and be the priority in the future for ALS.

Selectivity of herbicides applied to Brazilian tree species at post-emergence

The presence of weeds in silvicultural systems has been considered one of the main obstacles to the success of projects designed to recover degraded areas. The aim of this study was to evaluate the selectivity of herbicides applied at post-emergence in the initial growth of seedlings of capixingui (Croton floribundus), açoita-cavalo (Luehea divaricata), and guaritá (Astronium graveolens), in the municipalities of Jaboticabal and Junqueirópolis, state of São Paulo. The experimental design was completely randomized, with four replications, and the treatments consisted of herbicides (g a.i.·ha-1) clethodim + phenoxaprop-p-ethyl (50 + 50), sethoxydim (184), quizalofop-p-ethyl (75), nicosulfuron (50), fluazifop-p-butyl (125), fomesafen (225), haloxyfop-methyl (48), bentazon (720), chlorimuron-ethyl (15), in addition to control without herbicide. The characteristics analyzed were: plant height increase and visual phytointoxication at 7, 14, 21, 28, 35, and 42 days after herbicide application. At the end of the experiment, the shoots of the plants were removed to assess shoot dry matter. The herbicides clethodim + fenoxaprop-p-ethyl, fluazifop-p-butyl, and quizalofop-p-ethyl showed selective potential for the species capixingui, açoita-cavalo, and guaritá. The herbicide chlorimuron-ethyl caused mild intoxication symptoms when applied to seedlings of capixingui and açoita-cavalo; also, it was not selective for the guaritá species grown in Jaboticabal. All species showed selectivity to the herbicides sethoxydim, fomesafen, haloxyfop-methyl, and nicosulfuron, as their growth and initial development were not influenced. The herbicide bentazon caused high percentages of injury to açoita-cavalo plants in both cultivation places, but it did not influence the growth and development of the species.

The history behind ALS type 8: from the first phenotype description to the discovery of VAPB mutation / A história por detrás da ELA tipo 8: da primeira descrição do fenótipo à descoberta da mutação VAPB

ABSTRACT Over the past 68 years, the Finkel type late-onset adult autosomal dominant spinal muscular atrophy (SMA) that is allelic with amyotrophic lateral sclerosis-8 (ALS8) gained a genotype-phenotype correlation among the motor neuron diseases through the work of groups led by Zatz and Marques Jr.

RESUMO Nos últimos 68 anos, a atrofia muscular espinhal (AME), autossômica dominante, de início tardio, em adultos, conhecida como doença de Finkel, que é alélica com esclerose lateral amiotrófica tipo 8 (ELA8), ganhou uma correlação fenotípica e genotípica dentre as doenças do neurônio motor, a partir da colaboração dos grupos de Zatz e Marques Jr.

Recent developments on PET radiotracers for TSPO and their applications in neuroimaging

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases.

Natural compounds modulate the autophagy with potential implication of stroke

Stroke is considered a leading cause of mortality and neurological disability, which puts a huge burden on individuals and the community. To date, effective therapy for stroke has been limited by its complex pathological mechanisms. Autophagy refers to an intracellular degrading process with the involvement of lysosomes. Autophagy plays a critical role in maintaining the homeostasis and survival of cells by eliminating damaged or non-essential cellular constituents. Increasing evidence support that autophagy protects neuronal cells from ischemic injury. However, under certain circumstances, autophagy activation induces cell death and aggravates ischemic brain injury. Diverse naturally derived compounds have been found to modulate autophagy and exert neuroprotection against stroke. In the present work, we have reviewed recent advances in naturally derived compounds that regulate autophagy and discussed their potential application in stroke treatment.

Bulbar involvement time in spinal-onset amyotrophic lateral sclerosis: Effect on survival / 西安交通大学学报(医学版)

Objective: To explore the effect of bulbar involvement time on survival time of patients with spinal-onset amyotrophic lateral sclerosis (ALS). Methods: We followed up 168 patients with spinal-onset ALS admitted to our hospital from January 2, 2011 to December 31, 2017 until December 31, 2018. Univariate and multivariate analyses were performed to evaluate the affecting factors of the ALS patients' survival time. Kaplan-Meier analysis was made to evaluate the effects of bulbar involvement time on survival time. Results: COX multivariate analysis showed that the risk of death in age-onset <55 y patients was 0.72 times that in age-onset ≥55 y (P=0.09), the risk of death in diagnosis delay time <10.98 m patients was 2.64 times that ≥10.98 m (P<0.001); the risk of death in bulbar involvement time ≥11.5 m and bulbar uninvolvement was 0.30 and 0.32 times respectively that bulbar involvement time <11.5 m (P<0.001). Kaplan-Meier analysis showed differences among bulbar involvement time <11.5 m, ≥11.5 m and bulbar uninvolvement groups (median survival time 20.37 m vs. 40.6 m vs. 39.60 m, Test statistic =39.96, P<0.001). The 2-year, 3-year and 5-year survival rates were 32.17%, 10.80% and 0%, respectively, in bulbar involvement time <11.5 m patients; 89.20%, 57.24% and 10.53% in bulbar involvement time ≥11.5 months patients; and 62.16%, 38.39% and 10.53% in bulbar uninvolvement patients. Conclusion: Similar to the diagnosis delay time and whether to have taken riluzole, the occurrence of bulbar involvement at 11.5 month after onset was an independent risk factor affecting survival time in spinal-onset ALS. The median survival time in patients with bulbar involvement time <11.5 months was significantly shorter than that in patients with bulbar involvement time ≥11.5 months and bulbar uninvolvement.

Features of quantitative EEG in patients with amyotrophic lateral sclerosis and their relationship with cognitive impairment / 西安交通大学学报(医学版)

Objective: To investigate the characteristics of quantitative electroencephalogram (EEG) in patients with amyotrophic lateral sclerosis (ALS) and their relationship with cognitive impairment. Methods: We recruited 38 patients with ALS and 26 healthy controls. All the patients underwent quantitative EEG examination to obtain the relative power of each frequency band and calculate the slow wave ratio (δ+θ)/(α+β) as comparison indexes. Among them, 27 patients with ALS underwent the ECAS scale examination to assess their cognitive function. At the same time, 25 healthy controls underwent the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) to determine the cut-off of scale score. We compared the slow wave ratio in ALS patients with and without cognitive impairment according to the cut-off score. Results: The relative powers of δ and θ bands and slow wave ratios of quantitative EEG in ALS patients were significantly higher than those in healthy controls, and there was no significant difference in relative powers of α and β bands. In the comparison of slow wave ratios in different brain regions, the proportion of slow waves in the bilateral temporal-occipital regions and the right parietal areas was significantly higher than that in healthy controls. The slow wave ratio in the left temporal area was positively correlated with the course of ALS (correlation coefficient 0.405, P=0.05). The ECAS scale screening revealed that 33.3% of ALS patients had cognitive impairment. ALS patients with cognitive impairment had higher slow wave ratios in the frontal and temporal areas than patients without cognitive impairment. The ALS specific item score, ALS non-specific item score and the total score of ECAS were all negatively correlated with the slow wave ratios in the frontal and temporal areas. Conclusion: The changes of EEG activity in patients with ALS are mainly the increase of slow wave activity, which is significant in the temporal, parietal and occipital areas. The slow wave ratios in frontal and temporal areas of ALS patients are correlated with cognitive impairment.

Optimization of muscle selection for needle electromyography in amyotrophic lateral sclerosis / 西安交通大学学报(医学版)

Objective: To compare the diagnostic sensitivity of muscles in different regions on electromyography (EMG) to optimize and the muscle selection of needle electromyography in amyotrophic lateral sclerosis (ALS). To compare the diagnostic performance of revised El Escorial criteria (rEEC) and Awaji criteria (AwC) in ALS. Methods: Totally 198 ALS patients were recruited from ALS Clinic of The First Affiliated Hospital of Xi'an Jiaotong University and diagnosed with rEEC and AwC diagnostic criteria. Needle EMG was detected in muscles of bulbar, cervical, thoracal, and lumbosacral regions. Results: The muscle sensitivity in ALS regions (with or without clinical involvement) was consistent with that in the regions without clinical involvement. The diagnostic sensitivity of muscles were presented as follows: tongue (54.7% vs. 39.2%), trapezius (44.2% vs. 30.2%), lower orbicularis oris (33.2% vs. 20.7%), sternocleidomastoid (20% vs. 13.2%) in bulbar region, the first dorsal interosseus (93.8% vs. 77.3%), abductor pollicis brevis (92.8% vs. 72.7%), biceps (82% vs. 50%), deltoid (82% vs. 45.4%) in cervical region, thoracic paraspinal muscle 10 (86.5% vs. 85.3%) and rectus abdominis (49.5% vs. 49.3%) in thoracal region, the tibialis anterior (74.6% vs. 46.3%), and gastrocnemius (53.4% vs. 19.7%) in lumbosacral region. The diagnostic rate at AwC standard (75.3%) was significantly higher than that at rEEG standard (24.2%) (McNemar test P<0.001). Conclusion: The muscles of clinical affected region should be detected first, followed by the non-affected region in clinically suspected ALS. The tongue in bulbar region, the first dorsal interosseus in cervical region, thoracic paraspinal muscle 10 in thoracal region, tibialis anterior in lumbosacral region are recommended to detect in EMG protocol. The AwC criteria are suggested in ALS clinical diagnosis.

Non-motor symptoms in amyotrophic lateral sclerosis / 西安交通大学学报(医学版)

Amyotrophic lateral sclerosis (ALS) is a degenerative disease of the nervous system caused by the loss of motor neurons in the brain and spinal cord. At present, ALS is considered as a multi-system disease, with both motor and non-motor features. Motor neuron involvement usually begins in a single functional region (medulla oblongata, cervical vertebra, lumbosacral and thoracic vertebra) and gradually spreads throughout the motor system. Non-motor features may be caused by pathological damage from the motor region to the adjacent non-motor region or by other unknown causes. There is no uniform definition of non-motor features of ALS. Sometimes they refer to symptoms caused by damage to the non-pyramidal system, and sometimes they also include ALS syndrome. They can be divided into neuropsychiatric, autonomic, vascular and gastrointestinal dysfunctions. More than 50% of patients with ALS have symptoms of neuropsychiatric disorder, which are extremely heterogeneous. Such clinical heterogeneity is based on neuroimaging, genetics and neuropathology, which has updated the concept of ALS, leading to the present recognition of the spectrum disorder of ALS and frontotemporal dementia. The core features of the ALS diagnosis model should also be multi-axis diagnosis, using three main "diagnostic axes", i.e., axis to define motor neuron symptom variations, axis Ⅱ to define cognitive and behavioral dysfunction, and axis III to define other non-motor symptoms. This paper introduces ALS cognitive and behavioral dysfunction, ALS plus syndrome and other non-motor features associated with ALS so as to improve clinicians' understanding of managing the overall health status of ALS patients, make rational scientific evidence-based decisions and contribute to improving the quality of life of ALS patients.

Biomimetic carbon nanotubes for neurological disease therapeutics as inherent medication

Nowadays, nanotechnology is revolutionizing the approaches to different fields from manufacture to health. Carbon nanotubes (CNTs) as promising candidates in nanomedicine have great potentials in developing novel entities for central nervous system pathologies, due to their excellent physicochemical properties and ability to interface with neurons and neuronal circuits. However, most of the studies mainly focused on the drug delivery and bioimaging applications of CNTs, while neglect their application prospects as therapeutic drugs themselves. At present, the relevant reviews are not available yet. Herein we summarized the latest advances on the biomedical and therapeutic applications of CNTs and for neurological diseases treatments as inherent therapeutic drugs. The biological mechanisms of CNTs-mediated bio-medical effects and potential toxicity of CNTs were also intensely discussed. It is expected that CNTs will exploit further neurological applications on disease therapy in the near future.

A platform to understand amyotrophic lateral sclerosis (ALS) and extend human motor neurons longevity / Plataforma para empezar a comprender la esclerosis lateral amiotrófica (ELA) y extender la longevidad de neuronas motoras humanas

In vitro modeling of neurodegenerative diseases is now possible by using patient-derived induced pluripotent stem cells (iPS). Through them, it is nowadays conceivable to obtain human neurons and glia, and study diseases cellular and molecular mechanisms, an attribute that was previously unavailable to any human condition. Amyotrophic lateral sclerosis (ALS) is one of the diseases that has gained a rapid advance with iPS technology. By differentiating motor neurons from iPS cells of ALS- patients, we are studying the mechanisms underlying ALS- disease onset and progression. Here, we introduce a cellular platform to help maintain longevity of ALS iPS-motor neurons, a cellular feature relevant for most late-onset human diseases. Long term cultures of patient-derived iPS cells might prove to be critical for the development of personalized-drugs.

Actualmente es posible modelar in vitro enfermedades neurodegenerativas humanas mediante el uso de células madre pluripotentes inducidas (iPS) derivadas del paciente. A través de ellas, es hoy concebible obtener neuronas y glía humanas, y estudiar mecanismos celulares y moleculares de enfermedades, un atributo que anteriormente no era posible para ninguna condición humana. La esclerosis lateral amiotrófica (ELA) es una de las enfermedades que se ha beneficiado con la tecnología de iPS. Al diferenciar neuronas motoras de células iPS obtenidas de pacientes con ELA, hemos iniciado estudios sobre los mecanismos que subyacen a la aparición y progresión de la enfermedad. Aquí, presentamos el desarrollo de una plataforma celular que permite extender la longevidad de las neuronas motoras derivadas de iPS, una característica relevante para la mayoría de las enfermedades humanas de inicio tardío. Los cultivos a largo plazo de células iPS provenientes de pacientes pueden ser determinantes en el desarrollo de terapias asociadas a la medicina de precisión.

Airborne laser scanning for terrain modeling in the Amazon forest / Escaneamento laser aerotransportado para modelagem de terreno em floresta amazônica

Very few studies have been devoted to understanding the digital terrain model (DTM) creation for Amazon forests. DTM has a special and important role when airborne laser scanning is used to estimate vegetation biomass. We examined the influence of pulse density, spatial resolution, filter algorithms, vegetation density and slope on the DTM quality. Three Amazonian forested areas were surveyed with airborne laser scanning, and each original point cloud was reduced targeting to 20, 15, 10, 8, 6, 4, 2, 1, 0.75, 0.5 and 0.25 pulses per square meter based on a random resampling process. The DTM from resampled clouds was compared with the reference DTM produced from the original LiDAR data by calculating the deviation pixel by pixel and summarizing it through the root mean square error (RMSE). The DTM from resampled clouds were also evaluated considering the level of agreement with the reference DTM. Our study showed a clear trade-off between the return density and the horizontal resolution. Higher forest canopy density demanded higher return density or lower DTM resolution.

São poucos os estudos dedicados a entender a criação de modelo digital de terreno (MDT) para florestas amazônicas. O MDT tem uma importante função quando o escaneamento laser aerotransportado é usado para estimar a biomassa da vegetação. Examinamos a relação da densidade de pulsos, resolução espacial, algoritmos de filtragem, densidade da vegetação e inclinação do terreno com a qualidade do MDT. Três áreas de floresta amazônica foram sobrevoadas usando LiDAR aerotransportado. Cada nuvem de dados original teve sua densidade reduzida objetivando 20; 15; 10; 8; 6; 4; 2; 1; 0,75; 0,5 e 0,25 pulsos por metro quadrado, utilizando um processo de reamostragem aleatória. Os MDTs das nuvens reamostradas foram comparados com o MDT de referência, produzido a partir da nuvem original, calculando o desvio pixel a pixel e resumindo-o por meio do erro padrão da estimativa (RMSE). Os MDTs das nuvens reamostradas também foram avaliados quanto ao nível de correspondência com o MDT de referência. Houve uma clara compensação entre densidade de pontos e resolução horizontal. Dosséis mais densos exigem uma maior densidade de retornos, ou MDT com menor resolução.

Perspectives on the modeling of the neuromusculoskeletal system to investigate the influence of neurodegenerative diseases on sensorimotor control

Abstract Introduction The understanding of the neurophysiological mechanisms underlying movement control can be much furthered using computational models of the neuromusculoskeletal system. Biologically based multi-scale neuromusculoskeletal models have a great potential to provide new theories and explanations related to mechanisms behind muscle force generation at the molecular, cellular, synaptic, and systems levels. Albeit some efforts have been made to investigate how neurodegenerative diseases alter the dynamics of individual elements of the neuromuscular system, such diseases have not been analyzed from a systems viewpoint using multi-scale models. Overview and Perspectives This perspective article synthesizes what has been done in terms of multi-scale neuromuscular development and points to a few directions where such models could be extended so that they can be useful in the future to discover early predictors of neurodegenerative diseases, as well as to propose new quantitative clinical neurophysiology approaches to follow the course of improvements associated with different therapies (drugs or others). Concluding Remarks Therefore, this article will present how existing biologically based multi-scale models of the neuromusculoskeletal system could be expanded and adapted for clinical applications. It will point to mechanisms operating at different levels that would be relevant to be considered during model development, along with implications for interpreting experimental results from neurological patients.

Loss of VAPB Regulates Autophagy in a Beclin 1-Dependent Manner / 神经科学通报·英文版

Autophagy is an evolutionarily-conserved self-degradative process that maintains cellular homeostasis by eliminating protein aggregates and damaged organelles. Recently, vesicle-associated membrane protein-associated protein B (VAPB), which is associated with the familial form of amyotrophic lateral sclerosis, has been shown to regulate autophagy. In the present study, we demonstrated that knockdown of VAPB induced the up-regulation of beclin 1 expression, which promoted LC3 (microtubule-associated protein light chain 3) conversion and the formation of LC3 puncta, whereas overexpression of VAPB inhibited these processes. The regulation of beclin 1 by VAPB was at the transcriptional level. Moreover, knockdown of VAPB increased autophagic flux, which promoted the degradation of the autophagy substrate p62 and neurodegenerative disease proteins. Our study provides evidence that the regulation of autophagy by VAPB is associated with the autophagy-initiating factor beclin 1.

CRISPR/Cas9-mediated targeted gene correction in amyotrophic lateral sclerosis patient iPSCs

Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease with cellular and molecular mechanisms yet to be fully described. Mutations in a number of genes including SOD1 and FUS are associated with familial ALS. Here we report the generation of induced pluripotent stem cells (iPSCs) from fibroblasts of familial ALS patients bearing SOD1 and FUS mutations, respectively. We further generated gene corrected ALS iPSCs using CRISPR/Cas9 system. Genome-wide RNA sequencing (RNA-seq) analysis of motor neurons derived from SOD1 and corrected iPSCs revealed 899 aberrant transcripts. Our work may shed light on discovery of early biomarkers and pathways dysregulated in ALS, as well as provide a basis for novel therapeutic strategies to treat ALS.

The correlation between als3 gene expression and in vivo Candida albicans biofilm formation in mice / 中华传染病杂志

Objective To study the correlation between expression level of als3 gene and the in vivo biofilm formation of Candida albicans in mice.Methods The real-time polymerase chain reaction (PCR) assay was used to detect als3 gene expressions of the clinical Candida albicans isolates from February 2016 to August 2016 in Tianjing No.1 Central Hospital.According to the expression levels of als3 gene, Candida albicans isolates were divided into high and low-expression groups.Thirty C57 mice were randomly assigned to high-expression group (n=15), low-expression group (n=5) and blank group (n=5).Animal model of Candida albicans biofilm was established based on venous catheter and intraperitoneal injection of Candida albicans.Catheters were removed after two weeks;inverted microscope was used for the observation of Candida albicans biofilm formation and transmission electron microscope was used for the observation of its ultrastructure.After irrigating the catheter, the growth of Candida albicans was observed;real-time PCR was used to detect the expression levels of als3 gene 12, 24, and 48 h after the catheter being removed.In this study, t test was used for measurement data and chi-square test was used for rate comparisons.Results In high-expression group, 11 strains (11/15) formed biofilms.In als3 low-expression group, only one strain (1/10) formed biofilm.The difference between these two group was statistically significant (x2=9.64,P0.05).In the als3 high-expression group, the expression of als3 gene declined gradually during the biofilm formation.In the als3 low-expression group, the change of als3 gene expression was not obvious.The expressions of als3 gene over time between two groups were significantly different (t=8.7, 10.3 and 9.2, respectively, all P<0.05).Conclusion The high expression of als3 gene in Candida albicans facilitates the formation of biofilm in vivo.

Rapid Progression of Sporadic ALS in a Patient Carrying SOD1 p.Gly13Arg Mutation

Amyotrophic lateral sclerosis (ALS), the most common adult onset motor neuron disease, is pathologically characterized by progressive loss of the upper and lower motor neurons. Mutations in the Cu/Zn superoxide dismutase gene (SOD1) account for about 20% of familial ALS cases and a small percentage of sporadic ALS (SALS) cases, and have revealed a validated genotype-phenotype correlation. Herein, we report a p.Gly13Arg mutation in SOD1 exon 1 in a patient with SALS who presented with a rapidly progressive course, predominantly affecting the lower motor neurons. A 48-year-old man presented with progressive weakness and muscle atrophy of the left upper and lower limbs, followed by muscle fasciculation and cramping. The clinical features of the patient were clearly suggestive of ALS, and implied a sporadic form with rapid progression, predominantly affecting the lower motor neurons. Sequencing of the SOD1 gene by PCR revealed a missense mutation of G to C (c.37G>C) in exon 1, and amino acid substitution of glycine by arginine (p.Gly13Arg). This is the first case identifying the p.Gly13Arg mutation of SOD1 in the Korean population, and clinical assessments of this patient revealed a different phenotype compared with other cases.

Cysteine proteases as therapeutic targets: does selectivity matter? A systematic review of calpain and cathepsin inhibitors

Cysteine proteases continue to provide validated targets for treatment of human diseases. In neurodegenerative disorders, multiple cysteine proteases provide targets for enzyme inhibitors, notably caspases, calpains, and cathepsins. The reactive, active-site cysteine provides specificity for many inhibitor designs over other families of proteases, such as aspartate and serine; however, a) inhibitor strategies often use covalent enzyme modification, and b) obtaining selectivity within families of cysteine proteases and their isozymes is problematic. This review provides a general update on strategies for cysteine protease inhibitor design and a focus on cathepsin B and calpain 1 as drug targets for neurodegenerative disorders; the latter focus providing an interesting query for the contemporary assumptions that irreversible, covalent protein modification and low selectivity are anathema to therapeutic safety and efficacy.

Rosmarinic Acid Alleviates Neurological Symptoms in the G93A-SOD1 Transgenic Mouse Model of Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that affects motor neurons in the brain and spinal cord, resulting in paralysis of voluntary skeletal muscles and eventually death, usually within 2~3 years of symptom onset. The pathophysiology mechanism underlying ALS is not yet clearly understood. Moreover the available medication for treating ALS, riluzole, only modestly improves neurological symptoms and increases survival by a few months. Therefore, improved therapeutic strategies are urgently needed. In the present study, we investigated whether rosmarinic acid has a therapeutic potential to alleviate neurological deterioration in the G93A-SOD1 transgenic mouse model of ALS. Treatment of G93A-SOD1 transgenic mice with rosmarinic acid from 7 weeks of age at the dose of 400 mg/kg/day significantly extended survival, and relieved motor function deficits. Specifically, disease onset and symptom progression were delayed by more than one month. These symptomatic improvements were correlated with decreased oxidative stress and reduced neuronal loss in the ventral horns of G93A-SOD1 mice. These results support that rosmarinic acid is a potentially useful supplement for relieving ALS symptoms.