SBT-272 improves TDP-43 pathology in ALS upper motor neurons by modulating mitochondrial integrity, motility, and function.

Mitochondrial defects are one of the common underlying causes of neuronal vulnerability in neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most commonly observed proteinopathy. Disrupted inner mitochondrial membrane (IMM) reported in the upper motor neurons (UMNs) of ALS patients with TDP-43 pathology is recapitulated in the UMNs of well-characterized hTDP-43 mouse model of ALS. The construct validity, such as shared and common cellular pathology in mice and human, offers a unique opportunity to test treatment strategies that may translate to patients.

National-scale distribution of strontium isotope ratios in environmental samples from South Korea and its implications for provenance studies.

Successful application and accurate interpretation of strontium (Sr) isotope ratios (Sr/Sr) requires underlying information about the large-scale variabilities in their signatures from a variety of environmental samples, which can be correlated with the Sr isotopic signatures of underlying local geology. In this national-scale study, we analyzed Sr/Sr in soil, plants, stream water, and Chinese mystery snail (Cipangopaludina chinensis) shells collected from South Korea to evaluate large-scale spatial variabilities, interpret relationships among isotopic signatures of various sample types, and generate spatial distribution isoscapes reflecting the heterogeneity of isotopic signatures across South Korea. Non-parametric comparisons among environmental samples showed non-significant differences in their isotopic ratios.

NU-9 improves health of hSOD1 mouse upper motor neurons in vitro, especially in combination with riluzole or edaravone.

Even though amyotrophic lateral sclerosis (ALS) is a disease of the upper and lower motor neurons, to date none of the compounds in clinical trials have been tested for improving the health of diseased upper motor neurons (UMNs). There is an urgent need to develop preclinical assays that include UMN health as a readout. Since ALS is a complex disease, combinatorial treatment strategies will be required to address the mechanisms perturbed in patients.

Mitochondrial dysregulation occurs early in ALS motor cortex with TDP-43 pathology and suggests maintaining NAD balance as a therapeutic strategy.

Mitochondrial defects result in dysregulation of metabolomics and energy homeostasis that are detected in upper motor neurons (UMNs) with TDP-43 pathology, a pathology that is predominantly present in both familial and sporadic cases of amyotrophic lateral sclerosis (ALS). While same mitochondrial problems are present in the UMNs of ALS patients with TDP-43 pathology and UMNs of TDP-43 mouse models, and since pathologies are shared at a cellular level, regardless of species, we first analyzed the metabolite profile of both healthy and diseased motor cortex to investigate whether metabolomic changes occur with respect to TDP-43 pathology. High-performance liquid chromatography, high-resolution mass spectrometry and tandem mass spectrometry (HPLC-MS/MS) for metabolite profiling began to suggest that reduced levels of NAD+ is one of the underlying causes of metabolomic problems.

2-Year-Old and 3-Year-Old Italian ALS Patients with Novel Mutations: Identification of Key Metabolites in Their Serum and Plasma.

Pathogenic variants in have been detected mostly in juvenile cases of amyotrophic lateral sclerosis (ALS), affecting mainly children and teenagers. Patients with mutations demonstrate early onset cortical involvement in ALS. Currently, there are no effective treatment options.

Spatial distributions of strontium isotope ratios in human hair and tap water from South Korea.

Natural variations of Sr/Sr ratios in biological samples, such as human hair, provide a biological record of provenance. Spatial distribution maps reflecting heterogeneity in isotopic signatures across large geographical regions are helpful for discerning the provenance and mobility of organisms. In this national-scale study conducted across South Korea, we investigated the spatial distribution patterns of Sr/Sr ratios in human hair and tap water samples to determine their spatial variabilities and the relationships of isotopic signatures between hair and tap water.

Differential Epigenetic Signature of Corticospinal Motor Neurons in ALS.

Corticospinal motor neurons (CSMN) are an indispensable neuron population for the motor neuron circuitry. They are excitatory projection neurons, which collect information from different regions of the brain and transmit it to spinal cord targets, initiating and controlling motor function. CSMN degeneration is pronounced cellular event in motor neurons diseases, such as amyotrophic lateral sclerosis (ALS).

Improving mitochondria and ER stability helps eliminate upper motor neuron degeneration that occurs due to mSOD1 toxicity and TDP-43 pathology.

Background: Upper motor neurons (UMNs) are a key component of motor neuron circuitry. Their degeneration is a hallmark for diseases, such as hereditary spastic paraplegia (HSP), primary lateral sclerosis (PLS), and amyotrophic lateral sclerosis (ALS). Currently there are no preclinical assays investigating cellular responses of UMNs to compound treatment, even for diseases of the UMNs.

Better understanding the neurobiology of primary lateral sclerosis.

Primary lateral sclerosis (PLS) is a rare neurodegenerative disease characterized by progressive degeneration of upper motor neurons (UMNs). Recent studies shed new light onto the cellular events that are particularly important for UMN maintenance including intracellular trafficking, mitochondrial energy homeostasis and lipid metabolism. This review summarizes these advances including the role of Alsin as a gene linked to atypical forms of juvenile PLS, and discusses wider aspects of cellular pathology that have been observed in adult forms of PLS.

Major, trace and rare earth elements dynamics in decomposing litters on successional sites in a cool temperate region of South Korea.

Evaluating the decomposition-based change dynamics of various elements in plant litter is important for improving our understanding about their biogeochemical cycling in ecosystems. We have studied the concentrations of major, trace, and rare earth elements (REEs) (34 elements) in green tissue litter, and soil and their dynamics in the decomposing litters of successional annual fleabane (Erigeron annuus) and silvergrass (Miscanthus sinensis). Concentrations of major and trace elements in the litter of annual fleabane were 1.

Importance of lipids for upper motor neuron health and disease.

Building evidence reveals the importance of maintaining lipid homeostasis for the health and function of neurons, and upper motor neurons (UMNs) are no exception. UMNs are critically important for the initiation and modulation of voluntary movement as they are responsible for conveying cerebral cortex' input to spinal cord targets. To maintain their unique cytoarchitecture with a prominent apical dendrite and a very long axon, UMNs require a stable cell membrane, a lipid bilayer.

Extracellular Vesicles as Innovative Tool for Diagnosis, Regeneration and Protection against Neurological Damage.

Extracellular vesicles (EVs) have recently attracted a great deal of interest as they may represent a new biosignaling paradigm. According to the mode of biogenesis, size and composition, two broad categories of EVs have been described, exosomes and microvesicles. EVs have been shown to carry cargoes of signaling proteins, RNA species, DNA and lipids.

Datasets for spatial variation of O and H isotopes in waters and hair across South Korea.

The data presented here include the results of oxygen (δO) and hydrogen (δH) isotope analyses of water and human scalp hair samples collected from throughout the South Korea. The purpose of data collection was to generate isoscapes of oxygen and hydrogen isotopes for South Korea. To achieve the objective, we collected human scalp hair and three different types of water samples: groundwater, stream water and tap water.

Spatial variations in oxygen and hydrogen isotopes in waters and human hair across South Korea.

The spatial distribution of isotopic signatures in the form of isoscape is a valuable tool to map their spatial heterogeneity in various environmental settings. However, only limited information about δO and δH in water across South Korea is available and to our knowledge no study so far has tried to examine the isotopic heterogeneity of tap water and human scalp hair in South Korea. Here, we present the first national scale analyses of stream water, groundwater, tap water, and human scalp hair isoscapes for South Korea.

Mitoautophagy: A Unique Self-Destructive Path Mitochondria of Upper Motor Neurons With TDP-43 Pathology Take, Very Early in ALS.

Mitochondrial dysfunction is one of the converging paths for many neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS), and TDP-43 pathology is the most common proteinopathy detected in ALS and ALS/Frontotemporal lobar degeneration (ALS/FTLD). We recently identified mitochondrial problems in corticospinal motor neurons (CSMN) and in Betz cells of patients with TDP-43 pathology. However, the timing and the extent of mitochondrial defects, and their mode of degeneration have not been revealed.

MCP1-CCR2 and neuroinflammation in the ALS motor cortex with TDP-43 pathology.

Background: The involvement of non-neuronal cells and the cells of innate immunity has been attributed to the initiation and progression of ALS. TDP-43 pathology is observed in a broad spectrum of ALS cases and is one of the most commonly shared pathologies. The potential involvement of the neuroimmune axis in the motor cortex of ALS patients with TDP-43 pathology needs to be revealed.

Trends of major, minor and rare earth elements in decomposing litter in a cool temperate ecosystem, South Korea.

The decomposition dynamics of 34 different elements in four different litter types (foliar and woody litter) from Pinus densiflora (Korean red pine) and Castanea crenata (Korean chestnut) was investigated in a cool temperate ecosystem using the litterbag method. Two contrasting trends were observed in the dynamics of elements with accumulated mass loss of litter and carbon. Leaf litter of Korean chestnut, which was richer in elements, showed a general decrease in concentrations of elements with accumulated mass loss of litter and carbon on a dry mass basis during decomposition in the field.

Mitochondria, ER, and nuclear membrane defects reveal early mechanisms for upper motor neuron vulnerability with respect to TDP-43 pathology.

Insoluble aggregates containing TDP-43 are widely observed in the diseased brain, and defined as "TDP-43 pathology" in a spectrum of neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Alzheimer's disease and ALS with frontotemporal dementia. Here we report that Betz cells of patients with TDP-43 pathology display a distinct set of intracellular defects especially at the site of nuclear membrane, mitochondria and endoplasmic reticulum (ER). Numerous TDP-43 mouse models have been generated to discern the cellular and molecular basis of the disease, but mechanisms of neuronal vulnerability remain unknown.

Protein-protein interactions reveal key canonical pathways, upstream regulators, interactome domains, and novel targets in ALS.

Developing effective treatment strategies for neurodegenerative diseases require an understanding of the underlying cellular pathways that lead to neuronal vulnerability and progressive degeneration. To date, numerous mutations in 147 distinct genes are identified to be "associated" with, "modifier" or "causative" of amyotrophic lateral sclerosis (ALS). Protein products of these genes and their interactions helped determine the protein landscape of ALS, and revealed upstream modulators, key canonical pathways, interactome domains and novel therapeutic targets.

Hormone induced differential transcriptome analysis of Sertoli cells during postnatal maturation of rat testes.

Sertoli cells (Sc) are unique somatic cells of testis that are the target of both FSH and testosterone (T) and regulate spermatogenesis. Although Sc of neonatal rat testes are exposed to high levels of FSH and T, robust differentiation of spermatogonial cells becomes conspicuous only after 11-days of postnatal age. We have demonstrated earlier that a developmental switch in terms of hormonal responsiveness occurs in rat Sc at around 12 days of postnatal age during the rapid transition of spermatogonia A to B.

Absence of UCHL 1 function leads to selective motor neuropathy.

Objective: The aim of this study was to investigate the role of ubiquitin C-terminal hydrolase-L1 (UCHL1) for motor neuron circuitry and especially in spinal motor neuron (SMN) health, function, and connectivity.

Methods: Since mutations in UCHL1 gene leads to motor dysfunction in patients, we investigated the role of UCHL1 on SMN survival, axon health, and connectivity with the muscle, by employing molecular and cellular marker expression analysis and electrophysiological recordings, in healthy wild-type and Uchl1 (nm3419) (UCHL1-/-) mice, which lack all UCHL1 function.

Results: There is pure motor neuropathy with selective degeneration of the motor, but not sensory axons in the absence of UCHL1 function.

Advantages of pulsatile hormone treatment for assessing hormone-induced gene expression by cultured rat Sertoli cells.

In response to various hormonal (follicle-stimulating hormone [FSH] and testosterone [T]) and biochemical inputs, testicular Sertoli cells (Sc) produce factors that regulate spermatogenesis. A number of FSH- and T-responsive Sc-specific genes, necessary for spermatogenesis, have been identified to date. However, the hormone-induced in vitro expression pattern of most of these genes is reported to be inconsistent at various time points in primary rat Sc cultures.

Early-stage changes in natural (13)C and (15)N abundance and nutrient dynamics during different litter decomposition.

Decomposition, nutrient, and isotopic (δ(13)C and δ(15)N) dynamics during 1 year were studied for leaf and twig litters of Pinus densiflora, Castanea crenata, Erigeron annuus, and Miscanthus sinensis growing on a highly weathered soil with constrained nutrient supply using litterbags in a cool temperate region of South Korea. Decay constant (k/year) ranged from 0.58 to 1.

Absence of alsin function leads to corticospinal motor neuron vulnerability via novel disease mechanisms.

Mutations in the ALS2 gene result in early-onset amyotrophic lateral sclerosis, infantile-onset ascending hereditary spastic paraplegia and juvenile primary lateral sclerosis, suggesting prominent upper motor neuron involvement. However, the importance of alsin function for corticospinal motor neuron (CSMN) health and stability remains unknown. To date, four separate alsin knockout (Alsin(KO)) mouse models have been generated, and despite hopes of mimicking human pathology, none displayed profound motor function defects.

Transcriptome analysis of spermatogenically regressed, recrudescent and active phase testis of seasonally breeding wall lizards Hemidactylus flaviviridis.

Background: Reptiles are phylogenically important group of organisms as mammals have evolved from them. Wall lizard testis exhibits clearly distinct morphology during various phases of a reproductive cycle making them an interesting model to study regulation of spermatogenesis. Studies on reptile spermatogenesis are negligible hence this study will prove to be an important resource.