LRRK2 G2019S Mutated iPSC-Derived Endothelial Cells Exhibit Increased α-Synuclein, Mitochondrial Impairment, and Altered Inflammatory Responses.

The blood-brain barrier (BBB) serves as an interface between the bloodstream and the central nervous system. It limits the movement of molecules and immune cells, regulates the entry of nutrients, and removes waste products from the brain. The dysfunction of the BBB has been identified in Parkinson's disease (PD) but the role of the BBB and endothelial cells (ECs) has not been well studied.

The Roles of Cystatin B in the Brain and Pathophysiological Mechanisms of Progressive Myoclonic Epilepsy Type 1.

Progressive myoclonic epilepsy type 1 (EPM1) is an autosomal recessive disorder, also known as Unverricht-Lundborg disease (ULD). EPM1 patients suffer from photo-sensitive seizures, stimulus-sensitive myoclonus, nocturnal myoclonic seizures, ataxia and dysarthria. In addition, cerebral ataxia and impaired GABAergic inhibition are typically present.

The Mitochondrial m.3243A>G Mutation on the Dish, Lessons from In Vitro Models.

The m.3243A>G mutation in the tRNA Leu(UUR) gene (MT-TL1) is one of the most common pathogenic point mutations in human mtDNA. Patient symptoms vary widely and the severity of the disease ranges from asymptomatic to lethal.

Varied Responses to a High m.3243A>G Mutation Load and Respiratory Chain Dysfunction in Patient-Derived Cardiomyocytes.

The m.3243A>G mutation in mitochondrial is one of the most common pathogenic mitochondrial DNA mutations in humans. The clinical manifestations are highly heterogenous and the causes for the drastic clinical variability are unknown.

Modulating Mitochondrial DNA Heteroplasmy with Mitochondrially Targeted Endonucleases.

Mitochondria, mainly known as energy factories of eukaryotic cells, also exert several additional signaling and metabolic functions and are today recognized as major cellular biosynthetic and signaling hubs. Mitochondria possess their own genome (mitochondrial DNA-mtDNA), that encodes proteins essential for oxidative phosphorylation, and mutations in it are an important contributor to human disease. The mtDNA mutations often exist in heteroplasmic conditions, with both healthy and mutant versions of the mtDNA residing in patients' cells and the level of mutant mtDNA may vary between different tissues and organs and affect the clinical outcome of the disease.

The role of the meningeal lymphatic system in local meningeal inflammation and trigeminal nociception.

A system of lymphatic vessels has been recently characterized in the meninges, with a postulated role in 'cleaning' the brain via cerebral fluid drainage. As meninges are the origin site of migraine pain, we hypothesized that malfunctioning of the lymphatic system should affect the local trigeminal nociception. To test this hypothesis, we studied nociceptive and inflammatory mechanisms in the hemiskull preparations (containing the meninges) of K14-VEGFR3-Ig (K14) mice lacking the meningeal lymphatic system.

Neuron-astrocyte transmitophagy is altered in Alzheimer's disease.

Under physiological conditions in vivo astrocytes internalize and degrade neuronal mitochondria in a process called transmitophagy. Mitophagy is widely reported to be impaired in neurodegeneration but it is unknown whether and how transmitophagy is altered in Alzheimer's disease (AD). Here we report that the internalization of neuronal mitochondria is significantly increased in astrocytes isolated from AD mouse brains.

Functional Characterization of Mechanosensitive Piezo1 Channels in Trigeminal and Somatic Nerves in a Neuron-on-Chip Model.

Mechanosensitive ion channels, Piezo1 and 2, are activated by pressure and involved in diverse physiological functions, including senses of touch and pain, proprioception and many more. Understanding their function is important for elucidating the mechanosensitive mechanisms of a range of human diseases. Recently, Piezo channels were suggested to be contributors to migraine pain generation.

Generation of a human induced pluripotent stem cell line (UEFi003-A) carrying heterozygous A673T variant in amyloid precursor protein associated with a reduced risk of Alzheimer's disease.

A673T mutation in the amyloid precursor protein (APP) is a rare variant associated with a reduced risk of late-onset Alzheimer's disease (AD) and age-related cognitive decline. The A673T mutation decreases beta-amyloid (Aβ) production and aggregation in neuronal cultures in vitro. Here we have identified a Finnish non-diseased male individual carrying a heterozygous A673T mutation, obtained a skin biopsy sample from him, and generated an iPSC line using commercially available integration-free Sendai virus-based kit.

Metabolic alterations in Parkinson's disease astrocytes.

In Parkinson`s disease (PD), the loss of dopaminergic (DA) neurons in the substantia nigra pars compacta is associated with Lewy bodies arising from the accumulation of alpha-synuclein protein which leads ultimately to movement impairment. While PD has been considered a disease of the DA neurons, a glial contribution, in particular that of astrocytes, in PD pathogenesis is starting to be uncovered. Here, we report findings from astrocytes derived from induced pluripotent stem cells of LRRK2 G2019S mutant patients, with one patient also carrying a GBA N370S mutation, as well as healthy individuals.

Author Correction: Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias.

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

Defects in mtDNA replication challenge nuclear genome stability through nucleotide depletion and provide a unifying mechanism for mouse progerias.

Mitochondrial DNA (mtDNA) mutagenesis and nuclear DNA repair defects are considered cellular mechanisms of ageing. mtDNA mutator mice with increased mtDNA mutagenesis show signs of premature ageing. However, why patients with mitochondrial diseases, or mice with other forms of mitochondrial dysfunction, do not age prematurely remains unknown.

NF-E2-related factor 2 activation boosts antioxidant defenses and ameliorates inflammatory and amyloid properties in human Presenilin-1 mutated Alzheimer's disease astrocytes.

Alzheimer's disease (AD) is a common dementia affecting a vast number of individuals and significantly impairing quality of life. Despite extensive research in animal models and numerous promising treatment trials, there is still no curative treatment for AD. Astrocytes, the most common cell type of the central nervous system, have been shown to play a role in the major AD pathologies, including accumulation of amyloid plaques, neuroinflammation, and oxidative stress.

Regulation of Mother-to-Offspring Transmission of mtDNA Heteroplasmy.

mtDNA is present in multiple copies in each cell derived from the expansions of those in the oocyte. Heteroplasmy, more than one mtDNA variant, may be generated by mutagenesis, paternal mtDNA leakage, and novel medical technologies aiming to prevent inheritance of mtDNA-linked diseases. Heteroplasmy phenotypic impact remains poorly understood.

Astrocyte alterations in neurodegenerative pathologies and their modeling in human induced pluripotent stem cell platforms.

Astrocytes are the most abundant cell type in the brain. They were long considered only as passive support for neuronal cells. However, recent data have revealed many active roles for these cells both in maintenance of the normal physiological homeostasis in the brain as well as in neurodegeneration and disease.

Generation of a human induced pluripotent stem cell line (LL008 1.4) from a familial Alzheimer's disease patient carrying a double KM670/671NL (Swedish) mutation in APP gene.

A double mutation (KM670/671NL) in amyloid precursor protein gene (APP) is causative for familial Alzheimer's disease and has been shown to increase the total Aβ burden. Here we report the generation and characterization of an iPSC line from a fAD patient carrying APP KM670/671NL. The generated iPSCs retained the mutation, expressed pluripotency markers, showed a normal karyotype and differentiated into all three germ layers.

Generation of a human induced pluripotent stem cell line from a patient with a rare A673T variant in amyloid precursor protein gene that reduces the risk for Alzheimer's disease.

An amyloid precursor protein (APP) A673T mutation was found to be protective against Alzheimer's disease (AD) and cognitive decline in the Icelandic population and to associate with decreased levels of plasma β-amyloid in a Finnish population-based cohort. Human fibroblasts from a Finnish male individual carrying the protective mutation were used to generate integration-free induced pluripotent stem cell (iPSCs) line by Sendai virus technology. The iPSC line retained the mutation and expressed pluripotency markers, had a normal karyotype and differentiated into all three germ layers.

PSEN1 Mutant iPSC-Derived Model Reveals Severe Astrocyte Pathology in Alzheimer's Disease.

Alzheimer's disease (AD) is a common neurodegenerative disorder and the leading cause of cognitive impairment. Due to insufficient understanding of the disease mechanisms, there are no efficient therapies for AD. Most studies have focused on neuronal cells, but astrocytes have also been suggested to contribute to AD pathology.

Aβ and Inflammatory Stimulus Activate Diverse Signaling Pathways in Monocytic Cells: Implications in Retaining Phagocytosis in Aβ-Laden Environment.

: Accumulation of amyloid β (Aβ) is one of the main hallmarks of Alzheimer's disease (AD). The enhancement of Aβ clearance may provide therapeutic means to restrict AD pathology. The cellular responses to different forms of Aβ in monocytic cells are poorly known.

Mitochondrial DNA mutations in iPS cells: mtDNA integrity as standard iPSC selection criteria?

Somatic cells harbor random heteroplasmic mitochondrial DNA mutations, which are considered to contribute to aging. In this issue of , Perales‐Clemente (2016) show that mtDNA mutations, present at low levels in the starting fibroblasts, become enriched in iPS cells and lead to functional defects in iPS‐derived cells. In another recent study, Kang (2016) demonstrated that accumulation of mtDNA mutations of somatic origin in iPSCs is age related.

Mitochondria and mtDNA integrity in stem cell function and differentiation.

Stem cells require tight control of energy metabolism to maintain homeostasis. They possess few immature mitochondria, repress mitochondrial respiration and instead use glycolysis to produce energy, yet mitochondrial defects can lead to severe stem cell dysfunction. Recent studies have shown that mitochondrial mass, function and integrity are tightly controlled in stem cells and the integrity of the mitochondrial genome is equally important to nuclear genome integrity for proper stem cell homeostasis.

Trim37-deficient mice recapitulate several features of the multi-organ disorder Mulibrey nanism.

Mulibrey nanism (MUL) is a rare autosomal recessive multi-organ disorder characterized by severe prenatal-onset growth failure, infertility, cardiopathy, risk for tumors, fatty liver, and type 2 diabetes. MUL is caused by loss-of-function mutations in TRIM37, which encodes an E3 ubiquitin ligase belonging to the tripartite motif (TRIM) protein family and having both peroxisomal and nuclear localization. We describe a congenic Trim37 knock-out mouse (Trim37(-/-)) model for MUL.