Publications by authors named "Helen C Miranda"

Article Synopsis
  • VAPB is an ER membrane protein linked to familial ALS, specifically the mutation VAPB P56S, the exact mechanism of how it causes motor neuron disease is unclear.
  • In studies using iPSC-derived motor neurons, VAPB P56S was found to reduce neuronal firing, mitochondrial-ER contact, and caused aging-related drops in mitochondrial function while increasing sensitivity to ER stress.
  • Elevated levels of ATF4, a stress response marker, and reduced protein synthesis were observed in VAPB P56S neurons, with inhibition of the Integrated Stress Response (ISR) using ISRIB improving ALS symptoms, suggesting ISR as a therapeutic target.
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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.

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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.

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  • Neurons in the cerebellum connect temporally and spatially, forming important networks across the brain.
  • Organoid models are developed to replicate early human cerebellum differentiation, aiding in the study of related diseases that are hard to investigate in living subjects.
  • This study enhances existing protocols to create more mature cerebellar organoids, enabling the formation of various mature neuron types and their networks, facilitating research into Purkinje cells, granule cells, and interneurons for clinical and pharmaceutical uses.
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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.

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  • Tight regulation of mRNA isoform expression is key for neuronal development and function, but the proteins that control this process are not fully understood.
  • Researchers discovered that the RNA kinase CLP1 influences mRNA isoform expression by affecting how cleavage and polyadenylation (important steps in mRNA processing) occur.
  • In studies, motor neurons lacking CLP1 exhibited altered patterns in mRNA processing that led to reduced diversity in mRNA isoforms, a finding echoed in brain tissue samples from patients with neurodegenerative diseases, suggesting a potential common mechanism in these conditions.
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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).

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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.

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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.

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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.

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Article Synopsis
  • Spinobulbar muscular atrophy (SBMA) is an X-linked neuromuscular disease caused by an expansion of the polyglutamine sequence in the androgen receptor gene, leading to neurodegenerative damage due to protein aggregation.
  • CDK2 is found to phosphorylate the polyQ-AR, increasing its stability and toxicity, which is regulated by the AC/PKA signaling pathway.
  • Treatment with a PACAP analog showed promise in reducing harmful phosphorylation and improving symptoms in SBMA mice, highlighting a potential noninvasive therapy for the disease.
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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.

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  • SBMA is a progressive neuromuscular disease linked to a mutation in the androgen receptor, but its exact causes are still not fully understood.
  • NLK has been identified as a key factor that exacerbates SBMA, with the reduction of Nlk in mice leading to improved disease symptoms and increased lifespan.
  • The research reveals that NLK affects the mutated androgen receptor's function by promoting its aggregation and altering gene transcription, suggesting NLK as a potential target for new therapies for SBMA.
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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).

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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.

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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.

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Article Synopsis
  • The HIV-1 epidemic is rising in Brazil, prompting a study on the genetic factors related to HIV-1 infection, specifically the SDF1/CXCL12 gene polymorphism, in both asymptomatic and AIDS patients.
  • In a study of 161 asymptomatic and 617 AIDS patients, a small percentage of homozygous patients for the SDF1 mutation remained asymptomatic, and a notable difference in mortality rates was observed among AIDS patients based on their SDF1 genotype.
  • The findings suggest that the SDF1-3'A mutation may provide some late-stage protection against HIV-1 disease progression for the Brazilian population, although it had no significant effect on early disease markers like CD4+
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Article Synopsis
  • BDV is a virus that infects warm-blooded animals and has been studied in the context of psychiatric conditions among 30 patients with mood or psychotic disorders, compared to 30 healthy controls.
  • The presence of BDV p24 RNA was tested using specialized PCR techniques, revealing a higher detection rate in the patient group (33.33%) compared to controls (13.33%).
  • These findings suggest that BDV may play a role in the pathogenesis of psychiatric diseases, offering new insights into their development.
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  • The study examines the role of nitric oxide (*NO) in oxidative stress related to ischemia/reperfusion injury in rat gastrocnemius muscle using a chemiluminescence method to analyze lipid peroxides and antioxidant capacity.
  • Results showed a significant increase in oxidative stress markers after reperfusion, with initial increases in *NO levels and antioxidant consumption observed, which were modulated by nitric oxide synthase inhibitors like L-NAME and aminoguanidine.
  • The findings suggest that *NO is a key player in oxidative stress during reperfusion, with cNOS enzymes involved early and iNOS contributing to injury later in the process.
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