Scalable, optically-responsive human neuromuscular junction model reveals convergent mechanisms of synaptic dysfunction in familial ALS.

Neuromuscular junctions (NMJs) are specialized synapses that mediate communication between motor neurons and skeletal muscles and are essential for movement. The degeneration of this system can lead to symptoms observed in neuromuscular and motor neuron diseases. Studying these synapses and their degeneration has proven challenging.

Skeletal muscle TFEB signaling promotes central nervous system function and reduces neuroinflammation during aging and neurodegenerative disease.

Skeletal muscle has recently arisen as a regulator of central nervous system (CNS) function and aging, secreting bioactive molecules known as myokines with metabolism-modifying functions in targeted tissues, including the CNS. Here, we report the generation of a transgenic mouse with enhanced skeletal muscle lysosomal and mitochondrial function via targeted overexpression of transcription factor E-B (TFEB). We discovered that the resulting geroprotective effects in skeletal muscle reduce neuroinflammation and the accumulation of tau-associated pathological hallmarks in a mouse model of tauopathy.

Generation of advanced cerebellar organoids for neurogenesis and neuronal network development.

Neurons within the cerebellum form temporal-spatial connections through the cerebellum, and the entire brain. Organoid models provide an opportunity to model the early differentiation of the developing human cerebellum, which is difficult to study in vivo, and affords the opportunity to study neurodegenerative and neurodevelopmental diseases of the cerebellum. Previous cerebellar organoid models focused on early neuron generation and single cell activity.

Multiplexed microfluidic chip for cell co-culture.

Paracrine signaling is challenging to study , as conventional culture tools dilute soluble factors and offer little to no spatiotemporal control over signaling. Microfluidic chips offer potential to address both of these issues. However, few solutions offer both control over onset and duration of cell-cell communication, and high throughput.

Stress-induced perturbations in intracellular amino acids reprogram mRNA translation in osmoadaptation independently of the ISR.

The integrated stress response (ISR) plays a pivotal role in adaptation of translation machinery to cellular stress. Here, we demonstrate an ISR-independent osmoadaptation mechanism involving reprogramming of translation via coordinated but independent actions of mTOR and plasma membrane amino acid transporter SNAT2. This biphasic response entails reduced global protein synthesis and mTOR signaling followed by translation of SNAT2.

Suppression of premature transcription termination leads to reduced mRNA isoform diversity and neurodegeneration.

Tight regulation of mRNA isoform expression is essential for neuronal development, maintenance, and function; however, the repertoire of proteins that govern isoform composition and abundance remains incomplete. Here, we show that the RNA kinase CLP1 regulates mRNA isoform expression through suppression of proximal cleavage and polyadenylation. We found that human stem-cell-derived motor neurons without CLP1 or with the disease-associated CLP1 p.

Implications of mRNA translation dysregulation for neurological disorders.

The translation of information encoded in the DNA into functional proteins is one of the tenets of cellular biology. Cell survival and function depend on the tightly controlled processes of transcription and translation. Growing evidence suggests that dysregulation in mRNA translation plays an important role in the pathogenesis of several neurodevelopmental diseases, such as autism spectrum disorder (ASD) and fragile X syndrome (FXS) as well as neurodegenerative disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD) and amyotrophic lateral sclerosis (ALS).

An epilepsy-associated ACTL6B variant captures neuronal hyperexcitability in a human induced pluripotent stem cell model.

ACTL6B is a component of the neuronal BRG1/brm-associated factor (nBAF) complex, which is required for chromatin remodeling in postmitotic neurons. We recently reported biallelic pathogenic variants in ACTL6B in patients diagnosed with early infantile epileptic encephalopathy, subtype 76 (EIEE-76), presenting with severe, global developmental delay, epileptic encephalopathy, cerebral atrophy, and abnormal central nervous system myelination. However, the pathophysiological mechanisms underlying their phenotype is unknown.

Direct Generation of Human Cortical Organoids from Primary Cells.

The study of variations in human neurodevelopment and cognition is limited by the availability of experimental models. While animal models only partially recapitulate the human brain development, genetics, and heterogeneity, human-induced pluripotent stem cells can provide an attractive experimental alternative. However, cellular reprogramming and further differentiation techniques are costly and time-consuming and therefore, studies using this approach are often limited to a small number of samples.

Selective modulation of the androgen receptor AF2 domain rescues degeneration in spinal bulbar muscular atrophy.

Spinal bulbar muscular atrophy (SBMA) is a motor neuron disease caused by toxic gain of function of the androgen receptor (AR). Previously, we found that co-regulator binding through the activation function-2 (AF2) domain of AR is essential for pathogenesis, suggesting that AF2 may be a potential drug target for selective modulation of toxic AR activity. We screened previously identified AF2 modulators for their ability to rescue toxicity in a Drosophila model of SBMA.

Adenylyl cyclase activating polypeptide reduces phosphorylation and toxicity of the polyglutamine-expanded androgen receptor in spinobulbar muscular atrophy.

Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by polyglutamine (polyQ) expansion in the androgen receptor (AR) gene. SBMA belongs to the family of polyQ diseases, which are fatal neurodegenerative disorders mainly caused by protein-mediated toxic gain-of-function mechanisms and characterized by deposition of misfolded proteins in the form of aggregates. The neurotoxicity of the polyQ proteins can be modified by phosphorylation at specific sites, thereby providing the rationale for the development of disease-specific treatments.

PPAR-δ is repressed in Huntington's disease, is required for normal neuronal function and can be targeted therapeutically.

Huntington's disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. We found that peroxisome proliferator-activated receptor delta (PPAR-δ) interacts with HTT and that mutant HTT represses PPAR-δ-mediated transactivation. Increased PPAR-δ transactivation ameliorated mitochondrial dysfunction and improved cell survival of neurons from mouse models of HD.

Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a progressive neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR) protein. Despite extensive research, the exact pathogenic mechanisms underlying SBMA remain elusive. In this study, we present evidence that Nemo-like kinase (NLK) promotes disease pathogenesis across multiple SBMA model systems.

Polyglutamine-expanded androgen receptor interferes with TFEB to elicit autophagy defects in SBMA.

Macroautophagy (hereafter autophagy) is a key pathway in neurodegeneration. Despite protective actions, autophagy may contribute to neuron demise when dysregulated. Here we consider X-linked spinal and bulbar muscular atrophy (SBMA), a repeat disorder caused by polyglutamine-expanded androgen receptor (polyQ-AR).

A quantitative proteomic and transcriptomic comparison of human mesenchymal stem cells from bone marrow and umbilical cord vein.

Human mesenchymal stem cells (hMSCs) are adult multipotent cells that have high therapeutic potential due to their immunological properties. They can be isolated from several different tissues with bone marrow (BM) being the most common source. Because the isolation procedure is invasive, other tissues such as human umbilical cord vein (UCV) have been considered.

RNA from Borna disease virus in patients with schizophrenia, schizoaffective patients, and in their biological relatives.

Numerous interactions of the immune system with the central nervous system have been described recently. Mood and psychotic disorders, such as severe depression and schizophrenia, are both heterogeneous disorders regarding clinical symptomatology, the acuity of symptoms, the clinical course, the treatment response, and probably also the etiology. Detection of p24 RNA from Borna disease virus (BDV) by the reverse transcriptase polymerase chain reaction in patients with schizophrenia, schizoaffective disorder, and in their biological relatives was evaluated.

The effect of stromal cell-derived factor 1 (SDF1/CXCL12) genetic polymorphism on HIV-1 disease progression.

The human immunodeficiency virus type 1 (HIV-1) epidemic is increasing in Brazil, and little information has been reported about the genetic host factors related to HIV-1 infection in the Brazilian population. A polymorphism in the conserved 3' untranslated region of the stromal cell-derived factor 1 (SDF1/CXCL12) gene has been related either to resistance to HIV-1 infection and delayed progression to AIDS or to rapid disease progression and death. A longitudinal study was conducted to evaluate the association of the SDF1 polymorphism and the progression of HIV-1 infection in 161 asymptomatic patients infected with HIV-1 (ASYMPT) and 617 patients with AIDS (SYMPT) from Londrina and the surrounding region, southern Brazil.

Detection of Borna disease virus p24 RNA in peripheral blood cells from Brazilian mood and psychotic disorder patients.

Background: Borna disease virus (BDV) is a virus that naturally infects a broad range of warm-blooded animals. BDV is an enveloped virus, non-segmented, negative-stranded RNA genome and has an organization characteristic of a member of Bornaviridae in the order of Mononegavirale. In the present work we investigated the presence of BDV p24 RNA in peripheral blood cells from 30 psychiatric patients (19 with mood disorder and 11 with psychotic disorder) and 30 healthy volunteers as the control group.

Nitric oxide mediated oxidative stress injury in rat skeletal muscle subjected to ischemia/reperfusion as evaluated by chemiluminescence.

The involvement of nitric oxide (*NO) in oxidative stress in the rat gastrocnemius muscle subjected to ischemia/reperfusion injury was investigated using a specific and sensitive chemiluminescence (CL) method for measurement of both membrane lipid peroxide and total tissue antioxidant capacity (TRAP). In addition, inhibitors of nitric oxide synthase enzymes were used. The CL time-course curve increased dramatically after 1, 2, and 4 h of reperfusion, reaching values about 12 times higher than those of both control and ischemic rats.