A Gut-on-a-Chip Model to Study the Gut Microbiome-Nervous System Axis.

The human body is colonized by at least the same number of microbial cells as it is composed of human cells, and most of these microorganisms are located in the gut. Though the interplay between the gut microbiome and the host has been extensively studied, how the gut microbiome interacts with the enteric nervous system remains largely unknown. To date, a physiologically representative in vitro model to study gut microbiome-nervous system interactions does not exist.

Bone Tissue and the Nervous System: What Do They Have in Common?

Degenerative diseases affecting bone tissues and the brain represent important problems with high socio-economic impact. Certain bone diseases, such as osteoporosis, are considered risk factors for the progression of neurological disorders. Often, patients with neurodegenerative diseases have bone fractures or reduced mobility linked to osteoarthritis.

Generalising from conventional pipelines using deep learning in high-throughput screening workflows.

The study of complex diseases relies on large amounts of data to build models toward precision medicine. Such data acquisition is feasible in the context of high-throughput screening, in which the quality of the results relies on the accuracy of the image analysis. Although state-of-the-art solutions for image segmentation employ deep learning approaches, the high cost of manually generating ground truth labels for model training hampers the day-to-day application in experimental laboratories.

PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains T homeostasis during ageing.

Pyruvate dehydrogenase (PDH) is the gatekeeper enzyme of the tricarboxylic acid (TCA) cycle. Here we show that the deglycase DJ-1 (encoded by PARK7, a key familial Parkinson's disease gene) is a pacemaker regulating PDH activity in CD4 regulatory T cells (T cells). DJ-1 binds to PDHE1-β (PDHB), inhibiting phosphorylation of PDHE1-α (PDHA), thus promoting PDH activity and oxidative phosphorylation (OXPHOS).

Generation of isogenic control DJ-1-delP GC13 for the genetic Parkinson's disease-patient derived iPSC line DJ-1-delP (LCSBi008-A-1).

We describe the generation of an isogenic control cell line DJ-1-delP GC13 from an induced pluripotent stem cell (iPSC) line DJ-1-delP LCSBi008-A that was derived from fibroblasts obtained from a Parkinson's disease (PD) patient. Using CRISPR/Cas9 technology, we corrected the disease causing c.471_473delGCC homozygous mutation in the PARK7 gene leading to p.

Reproducible generation of human midbrain organoids for in vitro modeling of Parkinson's disease.

The study of human midbrain development and midbrain related diseases, like Parkinson's disease (PD), is limited by deficiencies in the currently available and validated laboratory models. Three dimensional midbrain organoids represent an innovative strategy to recapitulate some aspects of the complexity and physiology of the human midbrain. Nevertheless, also these novel organoid models exhibit some inherent weaknesses, including the presence of a necrotic core and batch-to-batch variability.

Midbrain Organoids: A New Tool to Investigate Parkinson's Disease.

The study of human 3D cell culture models not only bridges the gap between traditional 2D experiments and animal models, it also addresses processes that cannot be recapitulated by either of these traditional models. Therefore, it offers an opportunity to better understand complex biology including brain development. The brain organoid technology provides a physiologically relevant context, which holds great potential for its application in modeling neurological diseases.

Impaired serine metabolism complements LRRK2-G2019S pathogenicity in PD patients.

Parkinson's disease (PD) is a multifactorial disorder with complex etiology. The most prevalent PD associated mutation, LRRK2-G2019S is linked to familial and sporadic cases. Based on the multitude of genetic predispositions in PD and the incomplete penetrance of LRRK2-G2019S, we hypothesize that modifiers in the patients' genetic background act as susceptibility factors for developing PD.

FACS-Assisted CRISPR-Cas9 Genome Editing Facilitates Parkinson's Disease Modeling.

Genome editing and human induced pluripotent stem cells hold great promise for the development of isogenic disease models and the correction of disease-associated mutations for isogenic tissue therapy. CRISPR-Cas9 has emerged as a versatile and simple tool for engineering human cells for such purposes. However, the current protocols to derive genome-edited lines require the screening of a great number of clones to obtain one free of random integration or on-locus non-homologous end joining (NHEJ)-containing alleles.

Nurr1:RXRα heterodimer activation as monotherapy for Parkinson's disease.

Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by the loss of dopaminergic (DAergic) neurons in the substantia nigra and the gradual depletion of dopamine (DA). Current treatments replenish the DA deficit and improve symptoms but induce dyskinesias over time, and neuroprotective therapies are nonexistent. Here we report that Nuclear receptor-related 1 (Nurr1):Retinoid X receptor α (RXRα) activation has a double therapeutic potential for PD, offering both neuroprotective and symptomatic improvement.

Rapid and robust generation of long-term self-renewing human neural stem cells with the ability to generate mature astroglia.

Induced pluripotent stem cell bear the potential to differentiate into any desired cell type and hold large promise for disease-in-a-dish cell-modeling approaches. With the latest advances in the field of reprogramming technology, the generation of patient-specific cells has become a standard technology. However, directed and homogenous differentiation of human pluripotent stem cells into desired specific cell types remains an experimental challenge.

TRIM32 modulates pluripotency entry and exit by directly regulating Oct4 stability.

Induced pluripotent stem cells (iPSCs) have revolutionized the world of regenerative medicine; nevertheless, the exact molecular mechanisms underlying their generation and differentiation remain elusive. Here, we investigated the role of the cell fate determinant TRIM32 in modulating such processes. TRIM32 is essential for the induction of neuronal differentiation of neural stem cells by poly-ubiquitinating cMyc to target it for degradation resulting in inhibition of cell proliferation.

Elongation of axons during regeneration involves retinal crystallin beta b2 (crybb2).

Adult retinal ganglion cells (RGCs) can regenerate their axons in vitro. Using proteomics, we discovered that the supernatants of cultured retinas contain isoforms of crystallins with crystallin beta b2 (crybb2) being clearly up-regulated in the regenerating retina. Immunohistochemistry revealed the expression of crybb within the retina, including in filopodial protrusions and axons of RGCs.