An Enhanced Retroviral Vector for Efficient Genetic Manipulation and Selection in Mammalian Cells.

Introducing genetic material into hard-to-transfect mammalian cell lines and primary cells is often best achieved through retroviral infection. An ideal retroviral vector should offer a compact, selectable, and screenable marker while maximizing transgene delivery capacity. However, a previously published retroviral vector featuring an EGFP/Puromycin fusion protein failed to meet these criteria in our experiments.

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.

IL-3 receptor signalling suppresses chronic intestinal inflammation by controlling mechanobiology and tissue egress of regulatory T cells.

IL-3 has been reported to be involved in various inflammatory disorders, but its role in inflammatory bowel disease (IBD) has not been addressed so far. Here, we determined IL-3 expression in samples from patients with IBD and studied the impact of or deficiency on T cell-dependent experimental colitis. We explored the mechanical, cytoskeletal and migratory properties of and T cells using real-time deformability cytometry, atomic force microscopy, scanning electron microscopy, fluorescence recovery after photobleaching and and cell trafficking assays.

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.

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.

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.

Axon-Specific Mitochondrial Pathology in SPG11 Alpha Motor Neurons.

Pathogenic variants in are the most frequent cause of autosomal recessive complicated hereditary spastic paraplegia (HSP). In addition to spastic paraplegia caused by corticospinal degeneration, most patients are significantly affected by progressive weakness and muscle wasting due to alpha motor neuron (MN) degeneration. Mitochondria play a crucial role in neuronal health, and mitochondrial deficits were reported in other types of HSPs.

Unique signatures of stress-induced senescent human astrocytes.

Senescence was recently linked to neurodegeneration and astrocytes are one of the major cell types to turn senescent under neurodegenerative conditions. Senescent astrocytes were detected in Parkinson's disease (PD) patients' brains besides reactive astrocytes, yet the difference between senescent and reactive astrocytes is unclear. We aimed to characterize senescent astrocytes in comparison to reactive astrocytes and investigate differences and similarities.

Author Correction: A monocyte gene expression signature in the early clinical course of Parkinson's disease.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Demonstration of brain region-specific neuronal vulnerability in human iPSC-based model of familial Parkinson's disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by protein inclusions mostly composed of aggregated forms of α-synuclein (α-Syn) and by the progressive degeneration of midbrain dopaminergic neurons (mDANs), resulting in motor symptoms. While other brain regions also undergo pathologic changes in PD, the relevance of α-Syn aggregation for the preferential loss of mDANs in PD pathology is not completely understood yet. To elucidate the mechanisms of the brain region-specific neuronal vulnerability in PD, we modeled human PD using human-induced pluripotent stem cells (iPSCs) from familial PD cases with a duplication (Dupl) of the α-Syn gene (SNCA) locus.

Th17 cells: a promising therapeutic target for Parkinson's disease?

Parkinson's disease (PD) is the most common neurodegenerative movement disorder caused by the progressive loss of neurons in the midbrain and other brain regions. Only symptomatic treatment is currently available. Mounting evidence suggests that T cells are a key contributor to PD pathogenesis and neurodegeneration by a mechanism that requires further elucidation.

A monocyte gene expression signature in the early clinical course of Parkinson's disease.

Microglia are the main immune cells of the brain and express a large genetic pattern of genes linked to Parkinson's disease risk alleles. Monocytes like microglia are myeloid-lineage cells, raising the questions of the extent to which they share gene expression with microglia and whether they are already altered early in the clinical course of the disease. To decipher a monocytic gene expression signature in Parkinson's disease, we performed RNA-seq and applied the two-sample Kolmogorov-Smirnov test to identify differentially expressed genes between controls and patients with Parkinson's disease and changes in gene expression variability and dysregulation.

α-Synuclein oligomers induce early axonal dysfunction in human iPSC-based models of synucleinopathies.

α-Synuclein (α-Syn) aggregation, proceeding from oligomers to fibrils, is one central hallmark of neurodegeneration in synucleinopathies. α-Syn oligomers are toxic by triggering neurodegenerative processes in in vitro and in vivo models. However, the precise contribution of α-Syn oligomers to neurite pathology in human neurons and the underlying mechanisms remain unclear.

Th17 Lymphocytes Induce Neuronal Cell Death in a Human iPSC-Based Model of Parkinson's Disease.

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the progressive degeneration of midbrain neurons (MBNs). Recent evidence suggests contribution of the adaptive immune system in PD. Here, we show a role for human T lymphocytes as cell death inducers of induced pluripotent stem cell (iPSC)-derived MBNs in sporadic PD.

Impact of Swiprosin-1/Efhd2 on Adult Hippocampal Neurogenesis.

Swiprosin-1/Efhd2 (Efhd2) is highly expressed in the CNS during development and in the adult. EFHD2 is regulated by Ca binding, stabilizes F-actin, and promotes neurite extension. Previous studies indicated a dysregulation of EFHD2 in human Alzheimer's disease brains.

The Trojan horse - neuroinflammatory impact of T cells in neurodegenerative diseases.

Neuronal degeneration is a common mechanism of many neurological diseases including Parkinson's disease (PD), Alzheimer's disease (AD), and Multiple Sclerosis (MS). While AD and PD are classical neurodegenerative diseases, the primary pathology in MS is driven by autoimmune inflammation, attacking oligodendrocytes and thereby inducing neurodegeneration. In AD and PD, immune cells are also considered to play an important role in the disease progression.

Alpha-synuclein prevents the formation of spherical mitochondria and apoptosis under oxidative stress.

Oxidative stress (OS), mitochondrial dysfunction, and dysregulation of alpha-synuclein (aSyn) homeostasis are key pathogenic factors in Parkinson's disease. Nevertheless, the role of aSyn in mitochondrial physiology remains elusive. Thus, we addressed the impact of aSyn specifically on mitochondrial response to OS in neural cells.

Infiltrating T lymphocytes reduce myeloid phagocytosis activity in synucleinopathy model.

Background: Synucleinopathies comprise a group of neurodegenerative diseases associated with abnormal accumulation of α-synuclein. One of the key factors that contribute to the progression of synucleinopathies is neuroinflammation. However, the role of lymphocytes in synucleinopathies like Parkinson's disease (PD) remains largely unclear.

GSK3ß-dependent dysregulation of neurodevelopment in SPG11-patient induced pluripotent stem cell model.

Objective: Mutations in the spastic paraplegia gene 11 (SPG11), encoding spatacsin, cause the most frequent form of autosomal-recessive complex hereditary spastic paraplegia (HSP) and juvenile-onset amyotrophic lateral sclerosis (ALS5). When SPG11 is mutated, patients frequently present with spastic paraparesis, a thin corpus callosum, and cognitive impairment. We previously delineated a neurodegenerative phenotype in neurons of these patients.

The Ca2+ sensor protein swiprosin-1/EFhd2 is present in neurites and involved in kinesin-mediated transport in neurons.

Swiprosin-1/EFhd2 (EFhd2) is a cytoskeletal Ca2+ sensor protein strongly expressed in the brain. It has been shown to interact with mutant tau, which can promote neurodegeneration, but nothing is known about the physiological function of EFhd2 in the nervous system. To elucidate this question, we analyzed EFhd2-/-/lacZ reporter mice and showed that lacZ was strongly expressed in the cortex, the dentate gyrus, the CA1 and CA2 regions of the hippocampus, the thalamus, and the olfactory bulb.

Adult hippocampal neurogenesis in Parkinson's disease: impact on neuronal survival and plasticity.

In Parkinson's disease (PD) and other synucleinopathies, chronic neurodegeneration occurs within different areas of the central nervous system leading to progressive motor and nonmotor symptoms. The symptomatic treatment options that are currently available do not slow or halt disease progression. This highlights the need of a better understanding of disease mechanisms and disease models.

Intracellular alpha-synuclein affects early maturation of primary oligodendrocyte progenitor cells.

Myelin loss is a widespread neuropathological hallmark of the atypical parkinsonian disorder multiple system atrophy (MSA). On a cellular level, MSA is characterized by alpha-synuclein (aSyn)-positive glial cytoplasmic inclusions (GCIs) within mature oligodendrocytes leading to demyelination as well as axonal and neuronal loss. Oligodendrocyte progenitor cells (OPCs) represent a proliferative cell population distributed throughout the adult mammalian central nervous system.

Dysfunction of spatacsin leads to axonal pathology in SPG11-linked hereditary spastic paraplegia.

Hereditary spastic paraplegias are a group of inherited motor neuron diseases characterized by progressive paraparesis and spasticity. Mutations in the spastic paraplegia gene SPG11, encoding spatacsin, cause an autosomal-recessive disease trait; however, the precise knowledge about the role of spatacsin in neurons is very limited. We for the first time analyzed the expression and function of spatacsin in human forebrain neurons derived from human pluripotent stem cells including lines from two SPG11 patients and two controls.

Increased Th17 cell frequency and poor clinical outcome in rheumatoid arthritis are associated with a genetic variant in the IL4R gene, rs1805010.

Objective: The minor allele of the IL4R gene single-nucleotide polymorphism, rs1805010, confers impaired interleukin-4 (IL-4) signaling and has been associated with an aggressive destructive course of rheumatoid arthritis (RA). IL-4 inhibits the development of Th17 cells, a cell population recently identified as being prominent in RA patients and being associated with cartilage and bone destruction. The purpose of the present study was to investigate whether rs1805010 modulates Th17 cell development and, hence, subsequent clinical outcome in RA.