Alpha-synuclein fine-tunes neuronal response to pro-inflammatory cytokines.

Pro-inflammatory cytokines are emerging as neuroinflammatory mediators in Parkinson's disease (PD) due to their ability to act through neuronal cytokine receptors. Critical questions persist regarding the role of cytokines in neuronal dysfunction and their contribution to PD pathology. Specifically, the potential synergy of the hallmark PD protein alpha-synuclein (α-syn) with cytokines is of interest.

SARS-CoV-2 Spike Protein Induces Time-Dependent CTSL Upregulation in HeLa Cells and Alveolarspheres.

Autophagy and lysosomal pathways are involved in the cell entry of SARS-CoV-2 virus. To infect the host cell, the spike protein of SARS-CoV-2 binds to the cell surface receptor angiotensin-converting enzyme 2 (ACE2). To allow the fusion of the viral envelope with the host cell membrane, the spike protein has to be cleaved.

Neuroinflammatory disease signatures in SPG11-related hereditary spastic paraplegia patients.

Biallelic loss of SPG11 function constitutes the most frequent cause of complicated autosomal recessive hereditary spastic paraplegia (HSP) with thin corpus callosum, resulting in progressive multisystem neurodegeneration. While the impact of neuroinflammation is an emerging and potentially treatable aspect in neurodegenerative diseases and leukodystrophies, the role of immune cells in SPG11-HSP patients is unknown. Here, we performed a comprehensive immunological characterization of SPG11-HSP, including examination of three human postmortem brain donations, immunophenotyping of patients' peripheral blood cells and patient-specific induced pluripotent stem cell-derived microglia-like cells (iMGL).

A reversible state of hypometabolism in a human cellular model of sporadic Parkinson's disease.

Sporadic Parkinson's Disease (sPD) is a progressive neurodegenerative disorder caused by multiple genetic and environmental factors. Mitochondrial dysfunction is one contributing factor, but its role at different stages of disease progression is not fully understood. Here, we showed that neural precursor cells and dopaminergic neurons derived from induced pluripotent stem cells (hiPSCs) from sPD patients exhibited a hypometabolism.

Impact of Microbiome-Brain Communication on Neuroinflammation and Neurodegeneration.

The gut microbiome plays a pivotal role in maintaining human health, with numerous studies demonstrating that alterations in microbial compositions can significantly affect the development and progression of various immune-mediated diseases affecting both the digestive tract and the central nervous system (CNS). This complex interplay between the microbiota, the gut, and the CNS is referred to as the gut-brain axis. The role of the gut microbiota in the pathogenesis of neurodegenerative diseases has gained increasing attention in recent years, and evidence suggests that gut dysbiosis may contribute to disease development and progression.

Scaffold-Based (Matrigel™) 3D Culture Technique of Glioblastoma Recovers a Patient-like Immunosuppressive Phenotype.

Conventional 2D cultures are commonly used in cancer research though they come with limitations such as the lack of microenvironment or reduced cell heterogeneity. In this study, we investigated in what respect a scaffold-based (Matrigel™) 3D culture technique can ameliorate the limitations of 2D cultures. NGS-based bulk and single-cell sequencing of matched pairs of 2D and 3D models showed an altered transcription of key immune regulatory genes in around 36% of 3D models, indicating the reoccurrence of an immune suppressive phenotype.

Human Induced Pluripotent Stem Cell-Derived Pericytes as Scalable and Editable Source to Study Direct Lineage Reprogramming Into Induced Neurons.

Studying human somatic cell-to-neuron conversion using primary brain-derived cells as starting cell source is hampered by limitations and variations in human biopsy material. Thus, delineating the molecular variables that allow changing the identity of somatic cells, permit adoption of neuronal phenotypes, and foster maturation of induced neurons (iNs) is challenging. Based on our previous results that pericytes derived from the adult human cerebral cortex can be directly converted into iNs (Karow et al.

Proteolytic Activity of the Paracaspase MALT1 Is Involved in Epithelial Restitution and Mucosal Healing.

The paracaspase MALT1 is a crucial regulator of immune responses in various cellular contexts. Recently, there is increasing evidence suggesting that MALT1 might represent a novel key player in mucosal inflammation. However, the molecular mechanisms underlying this process and the targeted cell population remain unclear.

CRISPR/Cas9-mediated generation of hESC lines with homozygote and heterozygote p.R331W mutation in CTBP1 to model HADDTS syndrome.

C-terminal Binding Protein 1 (CTBP1) is a ubiquitously expressed transcriptional co-repressor and membrane trafficking regulator. A recurrent de novo c.991C>T mutation in CTBP1 leads to expression of p.

Neurometabolic Dysfunction in SPG11 Hereditary Spastic Paraplegia.

Background: Pathogenic variants in SPG11 cause the most common autosomal recessive complicated hereditary spastic paraplegia. Besides the prototypical combination of spastic paraplegia with a thin corpus callosum, obesity has increasingly been reported in this multisystem neurodegenerative disease. However, a detailed analysis of the metabolic state is lacking.

An alternative splicing modulator decreases mutant HTT and improves the molecular fingerprint in Huntington's disease patient neurons.

Huntington's disease (HD) is a neurodegenerative disorder caused by poly-Q expansion in the Huntingtin (HTT) protein. Here, we delineate elevated mutant HTT (mHTT) levels in patient-derived cells including fibroblasts and iPSC derived cortical neurons using mesoscale discovery (MSD) HTT assays. HD patients' fibroblasts and cortical neurons recapitulate aberrant alternative splicing as a molecular fingerprint of HD.

Druggable transcriptomic pathways revealed in Parkinson's patient-derived midbrain neurons.

Complex genetic predispositions accelerate the chronic degeneration of midbrain substantia nigra neurons in Parkinson's disease (PD). Deciphering the human molecular makeup of PD pathophysiology can guide the discovery of therapeutics to slow the disease progression. However, insights from human postmortem brain studies only portray the latter stages of PD, and there is a lack of data surrounding molecular events preceding the neuronal loss in patients.

The Gut-Immune-Brain Axis: An Important Route for Neuropsychiatric Morbidity in Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) comprises Crohn's disease (CD) and ulcerative colitis (UC) and is associated with neuropsychiatric symptoms like anxiety and depression. Both conditions strongly worsen IBD disease burden. In the present review, we summarize the current understanding of the pathogenesis of depression and anxiety in IBD.

Store-operated calcium entry is reduced in spastin-linked hereditary spastic paraplegia.

Pathogenic variants in SPAST, the gene coding for spastin, are the single most common cause of hereditary spastic paraplegia, a progressive motor neuron disease. Spastin regulates key cellular functions, including microtubule-severing and endoplasmic reticulum-morphogenesis. However, it remains unclear how alterations in these cellular functions due to SPAST pathogenic variants result in motor neuron dysfunction.

Translocation of Distinct Alpha Synuclein Species from the Nucleus to Neuronal Processes during Neuronal Differentiation.

Alpha synuclein (aSyn) and its aggregation are crucial for the neurodegeneration of Parkinson's disease (PD). aSyn was initially described in the nucleus and presynaptic nerve terminals. However, the biology of nuclear aSyn and the link of aSyn between subcellular compartments are less understood.

Primary cilia and SHH signaling impairments in human and mouse models of Parkinson's disease.

Parkinson's disease (PD) as a progressive neurodegenerative disorder arises from multiple genetic and environmental factors. However, underlying pathological mechanisms remain poorly understood. Using multiplexed single-cell transcriptomics, we analyze human neural precursor cells (hNPCs) from sporadic PD (sPD) patients.

Reduced synaptic activity and dysregulated extracellular matrix pathways in midbrain neurons from Parkinson's disease patients.

Several mutations that cause Parkinson's disease (PD) have been identified over the past decade. These account for 15-25% of PD cases; the rest of the cases are considered sporadic. Currently, it is accepted that PD is not a single monolithic disease but rather a constellation of diseases with some common phenotypes.

The Quest for Anti-α-Synuclein Antibody Specificity-Lessons Learnt From Flow Cytometry Analysis.

The accumulation of alpha-synuclein (aSyn) is the hallmark of a group of neurodegenerative conditions termed synucleopathies. Physiological functions of aSyn, including those outside of the CNS, remain elusive. However, a reliable and reproducible evaluation of aSyn protein expression in different cell types and especially in low-expressing cells is impeded by the existence of a huge variety of poorly characterized anti-aSyn antibodies and a lack of a routinely used sensitive detection methods.

Aberrant NOVA1 function disrupts alternative splicing in early stages of amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a fatal disease characterized by aberrant alternative splicing (AS). Nuclear loss and cytoplasmic accumulation of the splicing factor TDP-43 in motor neurons (MN) are hallmarks of ALS at late stages of the disease. However, it is unknown if altered AS is present before TDP-43 pathology occurs.

Organoids in gastrointestinal diseases: from experimental models to clinical translation.

We are entering an era of medicine where increasingly sophisticated data will be obtained from patients to determine proper diagnosis, predict outcomes and direct therapies. We predict that the most valuable data will be produced by systems that are highly dynamic in both time and space. Three-dimensional (3D) organoids are poised to be such a highly valuable system for a variety of gastrointestinal (GI) diseases.

Efficient and Easy Conversion of Human iPSCs into Functional Induced Microglia-like Cells.

Current protocols converting human induced pluripotent stem cells (iPSCs) into induced microglia-like cells (iMGL) are either dependent on overexpression of transcription factors or require substantial experience in stem-cell technologies. Here, we developed an easy-to-use two-step protocol to convert iPSCs into functional iMGL via: (1) highly efficient differentiation of hematopoietic progenitor cells (HPCs) from iPSCs, and (2) optimized maturation of HPCs to iMGL. A sequential harvesting approach led to an increased HPC yield.

Recombinant pro-CTSD (cathepsin D) enhances SNCA/α-Synuclein degradation in α-Synucleinopathy models.

Parkinson disease (PD) is a neurodegenerative disorder characterized by the abnormal intracellular accumulation of SNCA/α-synuclein. While the exact mechanisms underlying SNCA pathology are not fully understood, increasing evidence suggests the involvement of autophagy as well as lysosomal deficiencies. Because CTSD (cathepsin D) has been proposed to be the major lysosomal protease involved in SNCA degradation, its deficiency has been linked to the presence of insoluble SNCA conformers in the brain of mice and humans as well as to the transcellular transmission of SNCA aggregates.

Interaction of Alpha Synuclein and Microtubule Organization Is Linked to Impaired Neuritic Integrity in Parkinson's Patient-Derived Neuronal Cells.

Parkinson's disease (PD) is neuropathologically characterized by the loss of dopaminergic neurons and the deposition of aggregated alpha synuclein (aSyn). Mounting evidence suggests that neuritic degeneration precedes neuronal loss in PD. A possible underlying mechanism could be the interference of aSyn with microtubule organization in the neuritic development, as implied by several studies using cell-free model systems.