De novo missense variants in the PP2A regulatory subunit PPP2R2B in a neurodevelopmental syndrome: potential links to mitochondrial dynamics and spinocerebellar ataxias.

The heterotrimeric protein phosphatase 2A (PP2A) complex catalyzes about half of Ser/Thr dephosphorylations in eukaryotic cells. A CAG repeat expansion in the neuron-specific protein PP2A regulatory subunit PPP2R2B gene causes spinocerebellar ataxia type 12 (SCA12). We established five monoallelic missense variants in PPP2R2B (four confirmed as de novo) as a cause of intellectual disability with developmental delay (R149P, T246K, N310K, E37K, I427T).

A dynamical systems model for the total fission rate in Drp1-dependent mitochondrial fission.

Mitochondrial hyperfission in response to cellular insult is associated with reduced energy production and programmed cell death. Thus, there is a critical need to understand the molecular mechanisms coordinating and regulating the complex process of mitochondrial fission. We develop a nonlinear dynamical systems model of dynamin related protein one (Drp1)-dependent mitochondrial fission and use it to identify parameters which can regulate the total fission rate (TFR) as a function of time.

Astrocyte Mitochondria Are a Sensitive Target of PCB52 and its Human-Relevant Metabolites.

Polychlorinated biphenyls (PCBs) are industrial chemicals that are ubiquitously found in the environment. Exposure to these compounds has been associated with neurotoxic outcomes; however, the underlying mechanisms for such outcomes remain to be fully understood. Recent studies have shown that astrocytes, the most abundant glial cell type in the brain, are susceptible to PCB exposure as well as exposure to human-relevant metabolites of PCBs.

Driving Mitochondrial Fission Improves Cognitive, but not Motor Deficits in a Mouse Model of Ataxia of Charlevoix-Saguenay.

Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the SACS gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with Sacs knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction.

Driving mitochondrial fission improves cognitive, but not motor deficits in a mouse model of Ataxia of Charlevoix-Saguenay.

Autosomal-recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is caused by loss-of-function mutation in the gene, which encodes sacsin, a putative HSP70-HSP90 co-chaperone. Previous studies with knock-out (KO) mice and patient-derived fibroblasts suggested that SACSIN mutations inhibit the function of the mitochondrial fission enzyme dynamin-related protein 1 (Drp1). This in turn resulted in mitochondrial hyperfusion and dysfunction.

Molecular determinants and signaling effects of PKA RIα phase separation.

Spatiotemporal regulation of intracellular signaling molecules, such as the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures proper cellular function. Liquid-liquid phase separation (LLPS) of the ubiquitous PKA regulatory subunit RIα promotes cAMP compartmentation and signaling specificity. However, the molecular determinants of RIα LLPS remain unclear.

Protein Kinase A in neurological disorders.

Cyclic adenosine 3', 5' monophosphate (cAMP)-dependent Protein Kinase A (PKA) is a multi-functional serine/threonine kinase that regulates a wide variety of physiological processes including gene transcription, metabolism, and synaptic plasticity. Genomic sequencing studies have identified both germline and somatic variants of the catalytic and regulatory subunits of PKA in patients with metabolic and neurodevelopmental disorders. In this review we discuss the classical cAMP/PKA signaling pathway and the disease phenotypes that result from PKA variants.

Molecular Determinants and Signaling Effects of PKA RIα Phase Separation.

Spatiotemporal regulation of intracellular signaling molecules, such as the 3',5'-cyclic adenosine monophosphate (cAMP)-dependent protein kinase (PKA), ensures the specific execution of various cellular functions. Liquid-liquid phase separation (LLPS) of the ubiquitously expressed PKA regulatory subunit RIα was recently identified as a major driver of cAMP compartmentation and signaling specificity. However, the molecular determinants of RIα LLPS remain unclear.

B56δ long-disordered arms form a dynamic PP2A regulation interface coupled with global allostery and Jordan's syndrome mutations.

Intrinsically disordered regions (IDR) and short linear motifs (SLiMs) play pivotal roles in the intricate signaling networks governed by phosphatases and kinases. B56δ (encoded by ) is a regulatory subunit of protein phosphatase 2A (PP2A) with long IDRs that harbor a substrate-mimicking SLiM and multiple phosphorylation sites. De novo missense mutations in cause intellectual disabilities (ID), macrocephaly, Parkinsonism, and a broad range of neurological symptoms.

Serum Biomarkers of a Pro-Neuroinflammatory State May Define the Pre-Operative Risk for Postoperative Delirium in Spine Surgery.

Advances in spine surgery enable technically safe interventions in older patients with disabling spine disease, yet postoperative delirium (POD) poses a serious risk for postoperative recovery. This study investigates biomarkers of pro-neuroinflammatory states that may help objectively define the pre-operative risk for POD. This study enrolled patients aged ≥60 scheduled for elective spine surgery under general anesthesia.

Utilization of commercial collagens for preparing well-differentiated human beta cells for confocal microscopy.

Introduction: With technical advances, confocal and super-resolution microscopy have become powerful tools to dissect cellular pathophysiology. Cell attachment to glass surfaces compatible with advanced imaging is critical prerequisite but remains a considerable challenge for human beta cells. Recently, Phelps et al.

Role of A-Kinase Anchoring Protein 1 in Retinal Ganglion Cells: Neurodegeneration and Neuroprotection.

A-Kinase anchoring protein 1 (AKAP1) is a multifunctional mitochondrial scaffold protein that regulates mitochondrial dynamics, bioenergetics, and calcium homeostasis by anchoring several proteins, including protein kinase A, to the outer mitochondrial membrane. Glaucoma is a complex, multifactorial disease characterized by a slow and progressive degeneration of the optic nerve and retinal ganglion cells (RGCs), ultimately resulting in vision loss. Impairment of the mitochondrial network and function is linked to glaucomatous neurodegeneration.

Traffic noise inhibits inhibitory control in wild-caught songbirds.

Anthropogenic noise is ubiquitous across environments and can have negative effects on animals, ranging from physiology to community structure. Recent work with captive-bred zebra finches demonstrated that traffic noise also affects cognitive performance. We examined whether these results extend to animals that have experienced noise in the wild.

Extended regulation interface coupled to the allosteric network and disease mutations in the PP2A-B56δ holoenzyme.

An increasing number of mutations associated with devastating human diseases are diagnosed by whole-genome/exon sequencing. Recurrent missense mutations have been discovered in B56δ (encoded by ), a regulatory subunit of protein phosphatase 2A (PP2A), that cause intellectual disabilities (ID), macrocephaly, Parkinsonism, and a broad range of neurological symptoms. Single-particle cryo-EM structures show that the PP2A-B56δ holoenzyme possesses closed latent and open active forms.

Multimodal epigenetic changes and altered NEUROD1 chromatin binding in the mouse hippocampus underlie FOXG1 syndrome.

Forkhead box G1 (FOXG1) has important functions in neuronal differentiation and balances excitatory/inhibitory network activity. Thus far, molecular processes underlying FOXG1 function are largely unexplored. Here, we present a multiomics data set exploring how FOXG1 impacts neuronal maturation at the chromatin level in the mouse hippocampus.

The BBSome regulates mitochondria dynamics and function.

Objective: The essential role of mitochondria in regulation of metabolic function and other physiological processes has garnered enormous interest in understanding the mechanisms controlling the function of this organelle. We assessed the role of the BBSome, a protein complex composed of eight Bardet-Biedl syndrome (BBS) proteins, in the control of mitochondria dynamic and function.

Methods: We used a multidisciplinary approach that include CRISPR/Cas9 technology-mediated generation of a stable Bbs1 gene knockout hypothalamic N39 neuronal cell line.

Coupling to short linear motifs creates versatile PME-1 activities in PP2A holoenzyme demethylation and inhibition.

Protein phosphatase 2A (PP2A) holoenzymes target broad substrates by recognizing short motifs via regulatory subunits. PP2A methylesterase 1 (PME-1) is a cancer-promoting enzyme and undergoes methylesterase activation upon binding to the PP2A core enzyme. Here, we showed that PME-1 readily demethylates different families of PP2A holoenzymes and blocks substrate recognition in vitro.

Protein phosphatase 2A - structure, function and role in neurodevelopmental disorders.

Neurodevelopmental disorders (NDDs), including intellectual disability (ID), autism and schizophrenia, have high socioeconomic impact, yet poorly understood etiologies. A recent surge of large-scale genome or exome sequencing studies has identified a multitude of mostly de novo mutations in subunits of the protein phosphatase 2A (PP2A) holoenzyme that are strongly associated with NDDs. PP2A is responsible for at least 50% of total Ser/Thr dephosphorylation in most cell types and is predominantly found as trimeric holoenzymes composed of catalytic (C), scaffolding (A) and variable regulatory (B) subunits.

Perilipin 2 downregulation in β cells impairs insulin secretion under nutritional stress and damages mitochondria.

Perilipin 2 (PLIN2) is a lipid droplet (LD) protein in β cells that increases under nutritional stress. Downregulation of PLIN2 is often sufficient to reduce LD accumulation. To determine whether PLIN2 positively or negatively affects β cell function under nutritional stress, PLIN2 was downregulated in mouse β cells, INS1 cells, and human islet cells.

Distinct properties of Ca efflux from brain, heart and liver mitochondria: The effects of Na, Li and the mitochondrial Na/Ca exchange inhibitor CGP37157.

Mitochondrial Ca transport is essential for regulating cell bioenergetics, Ca signaling and cell death. Mitochondria accumulate Ca via the mitochondrial Ca uniporter (MCU), whereas Ca is extruded by the mitochondrial Na/Ca (mtNCX) and H/Ca exchangers. The balance between these processes is essential for preventing toxic mitochondrial Ca overload.

A Longitudinal Study of Parenting Conditions on Two Adult, North American River Otters' () Repetitive Behavior.

Captive animal welfare research focuses on husbandry, enrichment, enclosure space, visitor effects, and opportunities for species-typical behavior (e.g., foraging, territoriality, and social interaction).

The X-linked intellectual disability gene product and E3 ubiquitin ligase KLHL15 degrades doublecortin proteins to constrain neuronal dendritogenesis.

Proper brain development and function requires finely controlled mechanisms for protein turnover, and disruption of genes involved in proteostasis is a common cause of neurodevelopmental disorders. Kelch-like 15 (KLHL15) is a substrate adaptor for cullin3-containing E3 ubiquitin ligases, and KLHL15 gene mutations were recently described as a cause of severe X-linked intellectual disability. Here, we used a bioinformatics approach to identify a family of neuronal microtubule-associated proteins as KLHL15 substrates, which are themselves critical for early brain development.

Loss of AKAP1 triggers Drp1 dephosphorylation-mediated mitochondrial fission and loss in retinal ganglion cells.

Impairment of mitochondrial structure and function is strongly linked to glaucoma pathogenesis. Despite the widely appreciated disease relevance of mitochondrial dysfunction and loss, the molecular mechanisms underlying mitochondrial fragmentation and metabolic stress in glaucoma are poorly understood. We demonstrate here that glaucomatous retinal ganglion cells (RGCs) show loss of A-kinase anchoring protein 1 (AKAP1), activation of calcineurin (CaN) and reduction of dynamin-related protein 1 (Drp1) phosphorylation at serine 637 (Ser637).

Stress-Induced Cyclin C Translocation Regulates Cardiac Mitochondrial Dynamics.

Background Nuclear-to-mitochondrial communication regulating gene expression and mitochondrial function is a critical process following cardiac ischemic injury. In this study, we determined that cyclin C, a component of the Mediator complex, regulates cardiac and mitochondrial function in part by modifying mitochondrial fission. We tested the hypothesis that cyclin C functions as a transcriptional cofactor in the nucleus and a signaling molecule stimulating mitochondrial fission in response to stimuli such as cardiac ischemia.