Search results for "RC3"
showing 10 items of 896 documents
Oxidative Stress-Induced Axon Fragmentation Is a Consequence of Reduced Axonal Transport in Hereditary Spastic Paraplegia SPAST Patient Neurons
2020
Hereditary spastic paraplegia (HSP) is a group of inherited disorders characterized by progressive spasticity and paralysis of the lower limbs. Autosomal dominant mutations in SPAST gene account for ∼40% of adult-onset patients. We have previously shown that SPAST patient cells have reduced organelle transport and are therefore more sensitive to oxidative stress. To test whether these effects are present in neuronal cells, we first generated 11 induced pluripotent stem (iPS) cell lines from fibroblasts of three healthy controls and three HSP patients with different SPAST mutations. These cells were differentiated into FOXG1-positive forebrain neurons and then evaluated for multiple aspects …
Mitochondrial Function in Hereditary Spastic Paraplegia: Deficits in SPG7 but Not SPAST Patient-Derived Stem Cells
2020
Mutations in SPG7 and SPAST are common causes of hereditary spastic paraplegia (HSP). While some SPG7 mutations cause paraplegin deficiency, other SPG7 mutations cause increased paraplegin expression. Mitochondrial function has been studied in models that are paraplegin-deficient (human, mouse, and Drosophila models with large exonic deletions, null mutations, or knockout models) but not in models of mutations that express paraplegin. Here, we evaluated mitochondrial function in olfactory neurosphere-derived cells, derived from patients with a variety of SPG7 mutations that express paraplegin and compared them to cells derived from healthy controls and HSP patients with SPAST mutations, as …
Shank3 Mice Carrying the Human Q321R Mutation Display Enhanced Self-Grooming, Abnormal Electroencephalogram Patterns, and Suppressed Neuronal Excitab…
2019
Shank3, a postsynaptic scaffolding protein involved in regulating excitatory synapse assembly and function, has been implicated in several brain disorders, including autism spectrum disorders (ASD), Phelan-McDermid syndrome, schizophrenia, intellectual disability, and mania. Here we generated and characterized a Shank3 knock-in mouse line carrying the Q321R mutation (Shank3Q321R mice) identified in a human individual with ASD that affects the ankyrin repeat region (ARR) domain of the Shank3 protein. Homozygous Shank3Q321R/Q321R mice show a selective decrease in the level of Shank3a, an ARR-containing protein variant, but not other variants. CA1 pyramidal neurons in the Shank3Q321R/Q321R hip…
The Role of the Multifunctional BAG3 Protein in Cellular Protein Quality Control and in Disease
2017
In neurons, but also in all other cells the complex proteostasis network is monitored and tightly regulated by the cellular protein quality control (PQC) system. Beyond folding of newly synthesized polypeptides and their refolding upon misfolding the PQC also manages the disposal of aberrant proteins either by the ubiquitin-proteasome machinery or by the autophagic-lysosomal system. Aggregated proteins are primarily degraded by a process termed selective macroautophagy (or aggrephagy). One such recently discovered selective macroautophagy pathway is mediated by the multifunctional HSP70 co-chaperone BAG3 (BCL-2-associated athanogene 3). Under acute stress and during cellular aging, BAG3 in …
Boosting Action Observation and Motor Imagery to Promote Plasticity and Learning
2018
Neural Plasticity, 2018
TLR4 participates in the transmission of ethanol-induced neuroinflammation via astrocyte-derived extracellular vesicles
2019
Background Current evidence indicates that extracellular vesicles (EVs) participate in intercellular signaling, and in the regulation and amplification of neuroinflammation. We have previously shown that ethanol activates glial cells through Toll-like receptor 4 (TLR4) by triggering neuroinflammation. Here, we evaluate if ethanol and the TLR4 response change the release and inflammatory content of astrocyte-derived EVs, and whether these vesicles are capable of communicating with neurons by spreading neuroinflammation. Methods Cortical neurons and astrocytes in culture were used. EVs were isolated from the extracellular medium of the primary culture of the WT and TLR4-KO astrocytes treated …
Chronic Stress Modulates Interneuronal Plasticity: Effects on PSA-NCAM and Perineuronal Nets in Cortical and Extracortical Regions.
2018
Chronic stress has an important impact on the adult brain. However, most of the knowledge on its effects is focused on principal neurons and less on inhibitory neurons. Consequently, recent reports have begun to describe stress-induced alterations in the structure, connectivity and neurochemistry of interneurons. Some of these changes appear to be mediated by certain molecules particularly associated to interneurons, such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM) and components of the perineuronal nets (PNN), specialized regions of the extracellular matrix. These plasticity-related molecules modulate interneuronal structure and connectivity, particularly of …
MicroRNA-22 Controls Aberrant Neurogenesis and Changes in Neuronal Morphology After Status Epilepticus
2018
Prolonged seizures (status epilepticus, SE) may drive hippocampal dysfunction and epileptogenesis, at least partly, through an elevation in neurogenesis, dysregulation of migration and aberrant dendritic arborization of newly-formed neurons. MicroRNA-22 was recently found to protect against the development of epileptic foci, but the mechanisms remain incompletely understood. Here, we investigated the contribution of microRNA-22 to SE-induced aberrant adult neurogenesis. SE was induced by intraamygdala microinjection of kainic acid (KA) to model unilateral hippocampal neuropathology in mice. MicroRNA-22 expression was suppressed using specific oligonucleotide inhibitors (antagomir-22) and ne…
Deep Brain Stimulation and L-DOPA Therapy: Concepts of Action and Clinical Applications in Parkinson's Disease.
2018
L-DOPA is still the most effective pharmacological therapy for the treatment of motor symptoms in Parkinson's disease (PD) almost four decades after it was first used. Deep brain stimulation (DBS) is a safe and highly effective treatment option in patients with PD. Even though a clear understanding of the mechanisms of both treatment methods is yet to be obtained, the combination of both treatments is the most effective standard evidenced-based therapy to date. Recent studies have demonstrated that DBS is a therapy option even in the early course of the disease, when first complications arise despite a rigorous adjustment of the pharmacological treatment. The unique feature of this therapeu…
Pre-dopa Deep Brain Stimulation: Is Early Deep Brain Stimulation Able to Modify the Natural Course of Parkinson’s Disease?
2020
Deep brain stimulation (DBS) is an established therapy for the management of Parkinson's disease (PD). However, DBS is indicated as the disease progresses and motor complications derived from pharmacological therapy arise. Here, we evaluate the potential of DBS prior to levodopa (L-Dopa) in improving quality of life (QoL), challenging the state of the art for DBS therapy. We present data on clinical manifestation, decision finding during early indication to DBS, and trajectories after DBS. We further discuss current paradigms for DBS and hypothesize on possible mechanisms. Six patients, between 50 and 67 years old, presenting at least 5 years of PD symptoms, and without L-Dopa therapy initi…