Neuronal Degenerative Diseases Research Articles

Proteostasis in neurodegenerative diseases.

Proteostasis is essential for normal function of proteins and vital for cellular health and survival. Proteostasis encompasses all stages in the "life" of a protein, that is, from translation to functional performance and, ultimately, to degradation. Proteins need native conformations for function and in the presence of multiple types of stress, their misfolding and aggregation can occur. A coordinated network of proteins is at the core of proteostasis in cells. Among these, chaperones are required for maintaining the integrity of protein conformations by preventing misfolding and aggregation and guide those with abnormal conformation to degradation. The ubiquitin-proteasome system (UPS) and autophagy are major cellular pathways for degrading proteins. Although failure or decreased functioning of components of this network can lead to proteotoxicity and disease, like neuron degenerative diseases, underlying factors are not completely understood. Accumulating misfolded and aggregated proteins are considered major pathomechanisms of neurodegeneration. In this chapter, we have described the components of three major branches required for proteostasis-chaperones, UPS and autophagy, the mechanistic basis of their function, and their potential for protection against various neurodegenerative conditions, like Alzheimer's, Parkinson's, and Huntington's disease. The modulation of various proteostasis network proteins, like chaperones, E3 ubiquitin ligases, proteasome, and autophagy-associated proteins as therapeutic targets by small molecules as well as new and unconventional approaches, shows promise.

Single-Cell Analyses Reveal Necroptosis's Potential Role in Neuron Degeneration and Show Enhanced Neuron-Immune Cell Interaction in Parkinson's Disease Progression.

Parkinson's disease (PD) is a common neuron degenerative disease among the old, characterized by uncontrollable movements and an impaired posture. Although widely investigated on its pathology and treatment, the disease remains incompletely understood. Single-cell RNA sequencing (scRNA-seq) has been applied to the area of PD, providing valuable data for related research. However, few works have taken deeper insights into the causes of neuron death and cell-cell interaction between the cell types in the brain. Our bioinformatics analyses revealed necroptosis-related genes (NRGs) enrichment in neuron degeneration and selecting the cells by NRGs levels showed two subtypes within the main degenerative cell types in the midbrain. NRG-low subtype was largely replaced by NRG-high subtype in the patients, indicating the striking change of cell state related to necroptosis in PD progression. Moreover, we carried out cell-cell interaction analyses between cell types and found that microglia (MG)'s interaction strength with glutamatergic neuron (GLU), GABAergic neuron (GABA), and dopaminergic neuron (DA) was significantly upregulated in PD. Also, MG show much stronger interaction with NRG-high subtypes and a stronger cell killing function in PD samples. Additionally, we identified CLDN11 as a novel interaction pattern specific to necroptosis neurons and MG. We also found LEF1 and TCF4 as key transcriptional regulators in neuron degeneration. These findings suggest that MG were significantly overactivated in PD patients to clear abnormal neurons, especially the NRG-high cells, explaining the neuron inflammation in PD. Our analyses provide insights into the causes of neuron death and inflammation in PD from single-cell resolution, which could be seriously considered in clinical trials.

Clinical spectrum, biochemical profile and disease progression of Kennedy disease in an Indian cohort.

Kennedy disease (KD) is a slowly progressive lower motor neuron degenerative disease. The prevalence of KD is unknown in India. To describe the phenotypic and laboratory features of an Indian cohort of KD patients. A retrospective study was done on seven genetically confirmed KD patients based on demographic, clinical and laboratory details. Mean age at onset and presentation was 37 ± 11.9 and 44.6 ± 13.5 years respectively. Progressive asymmetric proximal and distal limb weakness was the commonest symptom (57.1%). All patients had motor symptoms along with non-specific symptoms such as cramps from the onset. Easy fatigability, decremental response along with ptosis were noted in two patients, which was a novel finding. Gynaecomastia and tongue wasting with fasciculations were universal findings. All five patients with nerve conduction studies showed sensorimotor neuropathy. Magnetic resonance imaging muscle done in two patients showed a prominent moth-eaten appearance in the thigh and posterior leg compartment in one patient. The mean cytosine-adenine-guanine repeats were 44 ± 3.7, and there was no association between age of onset or severity with repeat length. Only one patient required an assistive device for ambulation after 15 years of symptom onset. This study showed phenotypic heterogeneity in the Indian cohort. The age of onset was earlier with a slowly progressive indolent course as compared with other ethnic cohorts. This highlights the importance of considering the KD diagnosis in patients with the indolent course and suspected ALS diagnosis even with ptosis and fatigability in an appropriate clinical context.

Early detection of Alzheimer’s Disease using MRI images and deep learning techniques

AbstractBackgroundAlzheimer’s is a neurodegenerative disease that diminishes the capability of individuals to perform their daily activities. It is an irreversible disease once it is started not able to stop it but early detection of the disease can help to slow down the progression of it by starting early treatment. In this experiment, we use MRI images and clinical study data available at the Alzheimer’s Disease Neuroimaging Initiative data set to detect the different stages of Alzheimer’s and forecast the duration required for the conversion from mild cognitive impairment to Alzheimer’s. The clinical signs of Alzheimer’s disease are portrayed by Age, patient education details, the progression rate of disease, and cognitive information. Done experiment by using Machine learning and Deep learning techniques like multi perceptron networks, Random forest, SVM, and decision tree classifiers to do binary and multi‐classification of Alzheimer’s Disease(AD), Late Mild cognitive impairment (MCI), Early cognitive impairment (EMCI), and Cognitive control(CN).MethodDeep learning techniqueResultan average the model achieved 91.25% of precision indicates 91.25% total positive images are correctly classified, 91.25% of sensitivity indicates 91.25% of total images are detected remaining are not, and achieved 95.52% of accuracyConclusionAlzheimer’s is a neuron degenerative disease. Currently no treatment is available to cure AD or to stop progress of disease. But detection of dementia at its early stage might help individual family to think about their future regarding financial issues. In this work we tried our best to categorize the different phases of AD. We used a deep neural network and achieved an accuracy of 95.52%.

Exploring the Potential Utility of Psychedelic Therapy for Patients With Amyotrophic Lateral Sclerosis.

Background: Amyotrophic lateral sclerosis (ALS) is an aggressive, terminal neurodegenerative disease that causes death of motor neurons and has an average survival time of 3-4 years. ALS is the most common motor neuron degenerative disease and is increasing in prevalence. There is a pressing need for more effective ALS treatments as available pharmacotherapies do not reverse disease progression or provide substantial clinical benefit. Furthermore, despite psychological distress being highly prevalent in ALS patients, psychological treatments remain understudied. Psychedelics (i.e., serotonergic psychedelics and related compounds like ketamine) have seen a resurgence of research into therapeutic applications for treating a multitude of neuropsychiatric conditions, including psychiatric and existential distress in life-threatening illnesses. Methods: We conducted a narrative review to examine the potential of psychedelic assisted-psychotherapy (PAP) to alleviate psychiatric and psychospiritual distress in ALS. We also discussed the safety of using psychedelics in this population and proposed putative neurobiological mechanisms that may therapeutically intervene on ALS neuropathology. Results: PAP has the potential to treat psychological dimensions and may also intervene on neuropathological dimensions of ALS. Robust improvements in psychiatric and psychospiritual distress from PAP in other populations provide a strong rationale for utilizing this therapy to treat ALS-related psychiatric and existential distress. Furthermore, relevant neuroprotective properties of psychedelics warrant future preclinical trials to investigate this area in ALS models. Conclusion: PAP has the potential to serve as an effective treatment in ALS. Given the lack of effective treatment options, researchers should rigorously explore this therapy for ALS in future trials.

The Mixture of Gastrodia elata and Glycyrrhiza uralensis Attenuates Scopolamine-Induced Cognitive Disorder

Background: Cognitive disorders are symptoms of degenerative neuronal diseases such as Alzheimer’s disease (AD). This study evaluated the effects of a mixture of Gastrodiae elata (GE) and Glycyrrhizae uralensis (GU) (GGW) on scopolamine-treated cognitive function disorders in vivo. Methods: To induce memory impairment and cognitive disorder, C57BL/6 mice were intraperitoneally administered scopolamine. In the experimental period, the Y-maze, passive avoidance, and water maze tests were carried out to measure the ameliorative effect of GGW on cognitive function disorder. The expression of amyloid-β (Aβ), brain-derived neurotrophic factor (BDNF), and acetylcholinesterase (AChE) in the hippocampal tissues were measured. In addition, to assess the effect of GGW on brain tissue, tissues were stained using hematoxylin and eosin (H&E). Results: GGW treatment improved latencies in the Y-maze, water maze, and passive avoidance tests compared with scopolamine treatment alone. GGW administration downregulated Aβ and AChE expression. In addition, BDNF expression was upregulated by GGW administration. Conclusion: These results suggest that GGW ameliorates impaired cognitive function in a scopolamine-induced mouse model. In addition, GGW could control the pathway of scopolamine-induced cognitive disorders by regulating Aβ, AChE, and BDNF. These results suggest that GGW could be used as a treatment agent for cognitive dysfunction.

The Potential Roles of Ferroptosis in Pathophysiology and Treatment of Musculoskeletal Diseases-Opportunities, Challenges, and Perspectives.

Ferroptosis is different from other forms of cell death, such as apoptosis, autophagy, pyroptosis, and cuproptosis, mainly involving iron metabolism and lipid peroxidation. Ferroptosis plays an important role in various disease, such as malignant tumors, neuron-degenerative diseases, and cardiovascular diseases, and has become the focus of current research. Both iron overload and lipid peroxide accumulation contribute to the occurrence, development, and treatment of musculoskeletal diseases, such as osteoporosis, osteoarthritis, osteosarcoma, intervertebral disc degeneration, and spinal cord injury. For a better understanding of the potential roles ferroptosis may play in pathophysiology and treatment of common musculoskeletal disorders, this article briefly reviewed the relationship and possible mechanisms. Through an investigation of ferroptosis' role in musculoskeletal diseases' occurrence, development, and treatment, ferroptosis could offer new opportunities for clinical diagnosis and treatment.

Targeting Cellular Retinoic Acid Binding Protein 1 with Retinoic Acid-like Compounds to Mitigate Motor Neuron Degeneration.

All-trans-retinoic Acid (atRA) is the principal active metabolite of Vitamin A, essential for various biological processes. The activities of atRA are mediated by nuclear RA receptors (RARs) to alter gene expression (canonical activities) or by cellular retinoic acid binding protein 1 (CRABP1) to rapidly (minutes) modulate cytosolic kinase signaling, including calcium calmodulin-activated kinase 2 (CaMKII) (non-canonical activities). Clinically, atRA-like compounds have been extensively studied for therapeutic applications; however, RAR-mediated toxicity severely hindered the progress. It is highly desirable to identify CRABP1-binding ligands that lack RAR activity. Studies of CRABP1 knockout (CKO) mice revealed CRABP1 to be a new therapeutic target, especially for motor neuron (MN) degenerative diseases where CaMKII signaling in MN is critical. This study reports a P19-MN differentiation system, enabling studies of CRABP1 ligands in various stages of MN differentiation, and identifies a new CRABP1-binding ligand C32. Using the P19-MN differentiation system, the study establishes C32 and previously reported C4 as CRABP1 ligands that can modulate CaMKII activation in the P19-MN differentiation process. Further, in committed MN cells, elevating CRABP1 reduces excitotoxicity-triggered MN death, supporting a protective role for CRABP1 signaling in MN survival. C32 and C4 CRABP1 ligands were also protective against excitotoxicity-triggered MN death. The results provide insight into the potential of signaling pathway-selective, CRABP1-binding, atRA-like ligands in mitigating MN degenerative diseases.

Deubiquitinating enzyme YOD1 deubiquitinates and destabilizes α-synuclein

α-synuclein is one of the proteins involved in degenerative neuronal diseases such as Parkinson's disease (PD) or Lewy body dementia (LBD). The pathogenesis is imparted by the abnormal accumulation of α-synuclein resulting in the formation of a Lewy body (LB) and exerting neurotoxicity via an unknown mechanism. Regulation of α-synuclein is achieved by the ubiquitin-proteasome system (UPS), which influences protein homeostasis via inducing proteasome-dependent degradation by attaching a small molecule (ubiquitin) to the substrate. Deubiquitinating enzymes (DUBs) control the UPS by cleaving the peptide or isopeptide bond between ubiquitin and its substrate proteins. In a previous study, we found that YOD1 deubiquitinates and regulates the cellular function of neural precursor cell expressed developmentally down-regulated protein 4 (NEDD4), an E3 ligase that induces α-synuclein degradation. We hypothesized that YOD1 acts as a DUB involved in a modulated pathway of α-synuclein. In the current study, we found that YOD1 directly interacts with α-synuclein and deubiquitinates K6-, K11-, K29-, K33-, and K63-linked polyubiquitin chains on α-synuclein. Furthermore, YOD1 destabilizes α-synuclein protein stability by upregulating NEDD4. Collectively, this suggests the possibility that YOD1 is potentially a new regulator in the NEDD4-α-synuclein pathway.

Bcl-xL Promotes the Survival of Motor Neurons Derived from Neural Stem Cells.

Neural stem cell (NSC) transplantation creates new hope for the treatment of neurodegenerative disorders by direct differentiation into neurons. However, this technique is limited by poor survival and functional neuron deficiency. In this research study, we generated pro-survival murine NSCs (mNSCs) via the ectopic expression of Bcl-xL. A doxycycline (Dox)-inducible Ngn2-Isl1-Lhx3 system was also integrated into the mNSC genome. The four gene-modified mNSCs can rapidly and effectively differentiate into motor neurons after Dox treatments. Ectopic Bcl-xL could resist replating-induced stress, glutamate toxicity, neuronal apoptosis and remarkably promote the survival of motor neurons. Taken together, we established genetically modified mNSCs with improved survival, which may be useful for motor neuron degenerative diseases.

Network-based approach for targeting human kinases commonly associated with amyotrophic lateral sclerosis and cancer.

Amyotrophic Lateral Sclerosis (ALS) is a rare progressive and chronic motor neuron degenerative disease for which at present no cure is available. In recent years, multiple genes encode kinases and other causative agents for ALS have been identified. Kinases are enzymes that show pleiotropic nature and regulate different signal transduction processes and pathways. The dysregulation of kinase activity results in dramatic changes in processes and causes many other human diseases including cancers. In this study, we have adopted a network-based system biology approach to investigate the kinase-based molecular interplay between ALS and other human disorders. A list of 62 ALS-associated-kinases was first identified and then we identified the disease associated with them by scanning multiple disease-gene interaction databases to understand the link between the ALS-associated kinases and other disorders. An interaction network with 36 kinases and 381 different disorders associated with them was prepared, which represents the complexity and the comorbidity associated with the kinases. Further, we have identified 5 miRNAs targeting the majority of the kinases in the disease-causing network. The gene ontology and pathways enrichment analysis of those miRNAs were performed to understand their biological and molecular functions along with to identify the important pathways. We also identified 3 drug molecules that can perturb the disease-causing network by drug repurposing. This network-based study presented hereby contributes to a better knowledge of the molecular underpinning of comorbidities associated with the kinases associated with the ALS disease and provides the potential therapeutic targets to disrupt the highly complex disease-causing network.

Proteomics analysis indicates the involvement of immunity and inflammation in the onset stage of SOD1-G93A mouse model of ALS

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron degenerative disease, and the pathogenic mechanism that underlies ALS is still unclear. We analyzed the differentially expressed proteins (DEPs) in the spinal cord between SOD1-G93A transgenic mice at the onset stage and non-transgenic (NTG) littermates based on 4D label-free quantitative proteomics (4D-LFQ) with liquid chromatography-tandem mass spectrometry (LC-MS/MS). In our study, 189 DEPs were screened, of which 166 were up-regulated and 23 down-regulated. Clusters of Orthologous Groups (COG)/ EuKaryotic Orthologous Groups (KOG) classification, subcellular localization annotation, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment, clustering analysis and protein-protein interaction (PPI) network analyses were performed. Parallel reaction monitoring (PRM) analysis validated 48 proteins from immunity and inflammation-related pathways of KEGG. We described the function and distribution of DEPs, most of which were involved in the following pathways: complement and coagulation cascades, antigen processing and presentation, NF-kappa B signaling pathway, Retinoic acid-inducible gene I (RIG) -I-like receptor signaling pathway, the extracellular matrix-receptor (ECM-receptor) interaction, focal adhesion, phagosome and lysosome. PPI network analysis identified Fn1, Fga, Serpina1e and Serpina3n as potential biomarkers. Our discoveries broaden the view and expand our understanding of immunity and inflammation in ALS. SignificanceThis study gives a comprehensive description of DEPs in the spinal cord proteomics of SOD1-G93A mice at the onset period. Compared with a previous study focusing on progressive stage, we showed that immunity and inflammation play an important role at the onset stage of ALS. Several pathways validated by PRM bring new insight to the pathological mechanisms of ALS. The participation of RIG-I-like signaling pathway in ALS and potential biomarkers Fga, Fn1, Serpina1e and Serpina3n are supplements to existing knowledge.

Echium amoenum L. Ethanol Extract Protects Retinal Ganglion Cell after Glutamate and Optic Nerve Crush Injury

The development of low-cost and effective natural products for treating neuron degenerative diseases have proven to be safe and potentially effective. Echium amoenum L. (Boraginaceae) is an annual herb that grows wildly in Europe and western Asia. The aim of this study was to evaluate the neuroprotective properties of an ethanol extract of E. amoenum L. The effects of E. amoenum L. extract on oxidative stress were measured in the rat R28 retinal precursor cell line. Furthermore, the protective role of the extract on the glutamate-induced and optic nerve crush (ONC) injury-induced cell death were evaluated in vitro and in vivo, respectively. Our results showed that the ethanol extract of E. amoenum L. prevented the glutamate-induced decrease in cell viability and increase in cell death in R28 cells and suppressed the overproduction of ROS induced by glutamate. Moreover, the extract significantly inhibited microglial activation and optic nerve damage induced by ONC injury in mice. In addition, the mechanism was attributed to the ability of the extract to decrease NF-κB pathway activation and its downstream inflammatory cytokine production. In conclusion, E. amoenum L. ethanol extract had a potent neuroprotective effect against glutamate-induced and ONC-induced cell death. This is likely due to its antioxidant and anti-inflammatory properties.

The role of microRNAs in neurodegenerative diseases: a review.

MicroRNAs (miRNAs) are non-coding RNAs which are essential post-transcriptional gene regulators in various neuronal degenerative diseases and playact a key role in these physiological progresses. Neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, multiple sclerosis, and, stroke, are seriously threats to the life and health of all human health and life kind. Recently, various studies have reported that some various miRNAs can regulate the development of neurodegenerative diseases as well as act as biomarkers to predict these neuronal diseases conditions. Endogenic miRNAs such as miR-9, the miR-29 family, miR-15, and the miR-34 family are generally dysregulated in animal and cell models. They are involved in regulating the physiological and biochemical processes in the nervous system by targeting regulating different molecular targets and influencing a variety of pathways. Additionally, exogenous miRNAs derived from homologous plants and defined as botanmin, such as miR2911 and miR168, can be taken up and transferred by other species to be and then act analogously to endogenic miRNAs to regulate the physiological and biochemical processes. This review summarizes the mechanism and principle of miRNAs in the treatment of some neurodegenerative diseases, as well as discusses several types of miRNAs which were the most commonly reported in diseases. These miRNAs could serve as a study provided some potential biomarkers in neurodegenerative diseases might be an ideal and/or therapeutic targets for neurodegenerative diseases. Finally, the role accounted of the prospective exogenous miRNAs involved in mammalian diseases is described.Graphical abstract1. Listing a large number of neural-related miRNAs and sorting out their pathways.2. Classify and sort miRNAs according to their mechanism of action.3. Demonstrating the effects of up-regulation or down-regulation of each miRNAs on the nervous system.

Advance care planning in amyotrophic lateral sclerosis (ALS): study protocol for a qualitative longitudinal study with persons with ALS and their family carers.

IntroductionAmyotrophic lateral sclerosis (ALS) is an incurable motor neuron degenerative disease that has rapid progression and is associated with cognitive impairment. For people with ALS (pALS) and their family carers, advance care planning (ACP) is beneficial, as it can lead to feelings of control/relief and refusal of unwanted treatments. However, evidence concerning the experiences and preferences regarding ACP of pALS and their family carers, especially when their symptoms progress, is scarce. This article describes the protocol for a qualitative longitudinal study that aims to explore: (1) the experiences with ACP and the preferences for future care and treatment of pALS and their family carers and (2) how these experiences and preferences change over time.Methods and analysisA qualitative, longitudinal, multiperspective design. A total of eight to nine dyads (pALS and their family carers) will be recruited, and semistructured interviews administered every 3 months over a 9-month period. Qualitative longitudinal analysis involves content analysis via in-depth reading, followed by a two-step timeline method to describe changes in experiences and preferences within and across participants.Ethics and disseminationThis protocol has been approved by the central ethical committee of the University Hospital of Brussels, and local ethical committees of the other participating hospitals (B.U.N. B1432020000128). The results will be disseminated via the research group’s (endoflifecare.be) website, social media and newsletter and via presentations at national and international scientific conferences.

Differentiation Effect of Two Alkaloid Fractions from Vietnamese Lycopodiaceae on Mouse Neural Stem Cells

Various Lycopodium alkaloids have been studied for their various biological activities including anti-inflammatory, antioxidant, immunomodulatory, and neuroprotective activities. Moreover, these alkaloid compounds have high potential in the treatment of neuron degenerative disease. This study has been carried out to test the effect of Huperzia serrata (Thunb.) Trevis, and Lycopodium clavatum L alkaloid fractions on the mouse neural stem cells (NSCs). Firstly, the alkaloid fractions were used to verify its toxicity on NSCs. The multiple concentrations of alkaloid fractions from H. serrata (0.044; 0.088; 0.175; 0.35; 0.7; 1.4 mg/ml) and L. clavatum (0.031; 0.063; 0.125; 0.25; 0.50; 1.0; 2.0 mg/ml) have been used for the treatment of NSCs at period of 48h incubation. Results of the study suggested that the IC50 value of H. serrata and L. clavatum was 0.56 mg/ml and 0.50 mg/ml, respectively. Then, the NSCs were differentiated in the presence of 5 and 10 µg/ml of alkaloid fraction from H. serrata; 0.625 and 1.25 µg/ml of alkaloid fraction from L. clavatum for 6 days. Here, we observed the primary NSCs treated with alkaloid fraction extract from H. serrata showed the increased gene expression level of early neuron TUBB3 and neuron-specific cytoskeleton MAP2. On the other hand, the L. clavatum alkaloid fraction increased the expression of neural stem cell marker genes (Nestin and PAX6) and decreased neuron marker genes. In conclusion, these results established that alkaloid fraction from H. serrata promoted differentiation of the mouse NSCs to neuron cells, and L. clavatum extract had a capacity for stemness maintenance.

Expert consensus on preimplantation genetic testing for spinal muscular atrophy

Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron degenerative disease, which is the most common fatal neuromuscular disease in pediatrics with a high carrier frequency and can lead to progressive symmetrical muscle weakness and atrophy of the trunk and limbs. Preimplantation genetic testing (PGT) can be used to prevent the birth of children with SMA effectively. To standardize PGT technologies for SMA, experts from the fields of neurology, pediatrics and reproductive genetics have discussed and drafted this consensus for guiding its clinical application.

Motor neuron replacement therapy for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis is a motor neuron degenerative disease that is also known as Lou Gehrig’s disease in the United States, Charcot’s disease in France, and motor neuron disease in the UK. The loss of motor neurons causes muscle wasting, paralysis, and eventually death, which is commonly related to respiratory failure, within 3–5 years after onset of the disease. Although there are a limited number of drugs approved for amyotrophic lateral sclerosis, they have had little success at treating the associated symptoms, and they cannot reverse the course of motor neuron degeneration. Thus, there is still a lack of effective treatment for this debilitating neurodegenerative disorder. Stem cell therapy for amyotrophic lateral sclerosis is a very attractive strategy for both basic and clinical researchers, particularly as transplanted stem cells and stem cell-derived neural progenitor/precursor cells can protect endogenous motor neurons and directly replace the lost or dying motor neurons. Stem cell therapies may also be able to re-establish the motor control of voluntary muscles. Here, we review the recent progress in the use of neural stem cells and neural progenitor cells for the treatment of amyotrophic lateral sclerosis. We focus on MN progenitor cells derived from fetal central nervous system tissue, embryonic stem cells, and induced pluripotent stem cells. In our recent studies, we found that transplanted human induced pluripotent stem cell-derived motor neuron progenitors survive well, differentiate into motor neurons, and extend axons into the host white matter, not only in the rostrocaudal direction, but also along motor axon tracts towards the ventral roots in the immunodeficient rat spinal cord. Furthermore, the significant motor axonal extension after neural progenitor cell transplantation in amyotrophic lateral sclerosis models demonstrates that motor neuron replacement therapy could be a promising therapeutic strategy for amyotrophic lateral sclerosis, particularly as a variety of stem cell derivatives, including induced pluripotent stem cells, are being considered for clinical trials for various diseases.

Microglial TREM2 in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig's disease, is an aggressive motor neuron degenerative disease characterized by selective loss of both upper and lower motor neurons. The mechanisms underlying disease initiation and progression are poorly understood. The involvement of nonmotor neuraxis emphasizes the contribution of glial cells in disease progress. Microglia comprise a unique subset of glial cells and are the principal immune cells in the central nervous system (CNS). Triggering receptor expressed on myeloid cell 2 (TREM2) is a surface receptor that, within the CNS, is exclusively expressed on microglia and plays crucial roles in microglial proliferation, migration, activation, metabolism, and phagocytosis. Genetic evidence has linked TREM2 to neurodegenerative diseases including ALS, but its function in ALS pathogenesis is largely unknown. In this review, we summarize how microglial activation, with a specific focus on TREM2 function, affects ALS progression clinically and experimentally. Understanding microglial TREM2 function will help pinpoint the molecular target for ALS treatment.

Extracellular Vesicles as Innovative Treatment Strategy for Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a progressive and fatal motor neuron degenerative disease, and it is hard to diagnose in the early stage, and treatment means are limited, and the treatment effect is unsatisfactory. Therefore, exploring a new effective treatment strategy is urgently needed for ALS patients. Extracellular vesicles (EVs) are a heterogeneous group of natural membrane vesicles containing many bioactive substances, and they play important roles in the paracrine pathway and exhibit neuroprotection effects. A growing body of evidence shows that EVs have great application potential in diagnosis, treatment, and drug delivery in ALS, and they represent an innovative treatment strategy for ALS. In this review, we will briefly introduce the biogenesis of EVs and focus on discussing the role of EVs in ALS treatment to further enrich and boost the development of EVs as an innovative treatment strategy for ALS.