102 research outputs found
Transfer of Vesicles From Schwann Cells to Axons: a Novel Mechanism of Communication in the Peripheral Nervous System
Schwann cells (SCs) are the glial component of the peripheral nervous system, with essential roles during development and maintenance of axons, as well as during regenerative processes after nerve injury. SCs increase conduction velocities by myelinating axons, regulate synaptic activity at presynaptic nerve terminals and are a source of trophic factors to neurons. Thus, development and maintenance of peripheral nerves are crucially dependent on local signaling between SCs and axons. In addition to the classic mechanisms of intercellular signaling, the possibility of communication through secreted vesicles has been poorly explored to date. Interesting recent findings suggest the occurrence of lateral transfer mediated by vesicles from glial cells to axons that could have important roles in axonal growth and axonal regeneration. Here, we review the role of vesicular transfer from SCs to axons and propose the advantages of this means in supporting neuronal and axonal maintenance and regeneration after nerve damage
Cellular organisation of peripheral nerve and the neuromuscular junction
The organisation of cells in the peripheral nervous system is crucial for its proper
function. Action potential generation, conduction and synaptic transmission to the
muscle fibres are dependent not only on cells directly implicated in these functions
(i.e. neurons and muscle fibers) but also on accessory cells with important
modulatory roles. These cells are also essential for adaptive responses by the
peripheral nervous system during development, injury and pathological conditions.
Schwann cells represent one of the principal cellular components regulating nerve
function. In peripheral nerves, myelin-forming Schwann cells specify distinct
domains in the axon, allowing fast and efficient propagation of the action potential.
At the neuromuscular junction, terminal Schwann cells are necessary for stability of
motor nerve terminals and motor endplates and they are involved in plastic responses
of the neuromuscular system to injury and in disease.This thesis is a study of how the cellular organisation of the peripheral nerve and
neuromuscular junction determines their morphological and electrophysiological
characteristics as well as their functional role in plastic responses following
destabilizing stimuli. The mechanism by which Schwann cells regulate the length of
the myelinated segment over the axon is addressed and this parameter, i.e. the
internodal length, is shown experimentally for the first time as a key determinant of
nerve conduction velocity (Court et al., 2004). At the neuromuscular junction,
immunostaining with a panel of antibodies revealed a novel cell type, distinct from
Schwann cells and possibly related to fibroblasts. These cells lie outside the synaptic
basal lamina, but in adults they are highly restricted to the neuromuscular junction.
Studies of the development of the novel cells, and their reaction to nerve injury and
paralysis, suggest they play a crucial role in the maintenance and disposition of
motor nerve terminals and terminal Schwann cells. Finally, studies of periaxin null
mutant mice, which show a demyelinating neuropathy, yielded new insights into the
relationships between axons and Schwann cells at the neuromuscular junction.
Defects observed in morphology and electrophysiology of junctions in these mice
may contribute to their behavioural phenotype (i.e. trembling, weakness), suggesting
that disruption of nerve terminal-Schwann cell relationships may also contribute to
disability in demyelinating diseases
Molecular analysis of axonal-intrinsic and glial-associated co-regulation of axon degeneration
Mitochondria and Calcium Regulation as Basis of Neurodegeneration Associated With Aging
Age is the main risk factor for the onset of neurodegenerative diseases. A decline of mitochondrial function has been observed in several age-dependent neurodegenerative diseases and may be a major contributing factor in their progression. Recent findings have shown that mitochondrial fitness is tightly regulated by Ca2+ signals, which are altered long before the onset of measurable histopathology hallmarks or cognitive deficits in several neurodegenerative diseases including Alzheimer’s disease (AD), the most frequent cause of dementia. The transfer of Ca2+ from the endoplasmic reticulum (ER) to the mitochondria, facilitated by the presence of mitochondria-associated membranes (MAMs), is essential for several physiological mitochondrial functions such as respiration. Ca2+ transfer to mitochondria must be finely regulated because excess Ca2+ will disturb oxidative phosphorylation (OXPHOS), thereby increasing the generation of reactive oxygen species (ROS) that leads to cellular damage observed in both aging and neurodegenerative diseases. In addition, excess Ca2+ and ROS trigger the opening of the mitochondrial transition pore mPTP, leading to loss of mitochondrial function and cell death. mPTP opening probably increases with age and its activity has been associated with several neurodegenerative diseases. As Ca2+ seems to be the initiator of the mitochondrial failure that contributes to the synaptic deficit observed during aging and neurodegeneration, in this review, we aim to look at current evidence for mitochondrial dysfunction caused by Ca2+ miscommunication in neuronal models of neurodegenerative disorders related to aging, with special emphasis on AD
An optimized comparative proteomic approach as a tool in neurodegenerative disease research.
Recent advances in proteomic technologies now allow unparalleled assessment of the molecular composition of a wide range of sample types. However, the application of such technologies and techniques should not be undertaken lightly. Here, we describe why the design of a proteomics experiment itself is only the first step in yielding high-quality, translatable results. Indeed, the effectiveness and/or impact of the majority of contemporary proteomics screens are hindered not by commonly considered technical limitations such as low proteome coverage but rather by insufficient analyses. Proteomic experimentation requires a careful methodological selection to account for variables from sample collection, through to database searches for peptide identification to standardised post-mass spectrometry options directed analysis workflow, which should be adjusted for each study, from determining when and how to filter proteomic data to choosing holistic versus trend-wise analyses for biologically relevant patterns. Finally, we highlight and discuss the difficulties inherent in the modelling and study of the majority of progressive neurodegenerative conditions. We provide evidence (in the context of neurodegenerative research) for the benefit of undertaking a comparative approach through the application of the above considerations in the alignment of publicly available pre-existing data sets to identify potential novel regulators of neuronal stability
β1 integrin activates Rac1 in Schwann cells to generate radial lamellae during axonal sorting and myelination
Myelin is a multispiraled extension of glial membrane that surrounds axons. How glia extend a surface many-fold larger than their body is poorly understood. Schwann cells are peripheral glia and insert radial cytoplasmic extensions into bundles of axons to sort, ensheath, and myelinate them. Laminins and β1 integrins are required for axonal sorting, but the downstream signals are largely unknown. We show that Schwann cells devoid of β1 integrin migrate to and elongate on axons but cannot extend radial lamellae of cytoplasm, similar to cells with low Rac1 activation. Accordingly, active Rac1 is decreased in β1 integrin–null nerves, inhibiting Rac1 activity decreases radial lamellae in Schwann cells, and ablating Rac1 in Schwann cells of transgenic mice delays axonal sorting and impairs myelination. Finally, expressing active Rac1 in β1 integrin–null nerves improves sorting. Thus, increased activation of Rac1 by β1 integrins allows Schwann cells to switch from migration/elongation to the extension of radial membranes required for axonal sorting and myelination
Necroptosis inhibition counteracts neurodegeneration, memory decline and key hallmarks of aging, promoting brain rejuvenation.:Necroptosis inhibition prevents brain aging
Altered mitochondrial bioenergetics are responsible for the delay in Wallerian degeneration observed in neonatal mice
Aβ oligomers trigger necroptosis-mediated neurodegeneration via microglia activation in Alzheimer’s disease
Alzheimer’s disease (AD) is a major adult-onset neurodegenerative condition with no available treatment. Compelling reports point amyloid-β (Aβ) as the main etiologic agent that triggers AD. Although there is extensive evidence of detrimental crosstalk between Aβ and microglia that contributes to neuroinflammation in AD, the exact mechanism leading to neuron death remains unknown. Using postmortem human AD brain tissue, we show that Aβ pathology is associated with the necroptosis effector pMLKL. Moreover, we found that the burden of Aβ oligomers (Aβo) correlates with the expression of key markers of necroptosis activation. Additionally, inhibition of necroptosis by pharmacological or genetic means, reduce neurodegeneration and memory impairment triggered by Aβo in mice. Since microglial activation is emerging as a central driver for AD pathogenesis, we then tested the contribution of microglia to the mechanism of Aβo-mediated necroptosis activation in neurons. Using an in vitro model, we show that conditioned medium from Aβo-stimulated microglia elicited necroptosis in neurons through activation of TNF-α signaling, triggering extensive neurodegeneration. Notably, necroptosis inhibition provided significant neuronal protection. Together, these findings suggest that Aβo-mediated microglia stimulation in AD contributes to necroptosis activation in neurons and neurodegeneration. As necroptosis is a druggable degenerative mechanism, our findings might have important therapeutic implications to prevent the progression of AD.España Ministry of Science and Innovation (MICIN) State Research Agency grants PID2019-107090RA-I00España Ministerio de Ciencia e Innovación, Programa Ramon y Caja RYC-2017-21879 (to IMG) and grants from NIH R01AG059321 and R01AG061069 (to CS)
Insulin-like growth factor 2 (IGF2) protects against Huntington's disease through the extracellular disposal of protein aggregates
Impaired neuronal proteostasis is a salient feature of many neurodegenerative diseases, highlighting alterations in the function of the endoplasmic reticulum (ER). We previously reported that targeting the transcription factor XBP1, a key mediator of the ER stress response, delays disease progression and reduces protein aggregation in various models of neurodegeneration. To identify disease modifier genes that may explain the neuroprotective effects of XBP1 deficiency, we performed gene expression profiling of brain cortex and striatum of these animals and uncovered insulin-like growth factor 2 (Igf2) as the major upregulated gene. Here, we studied the impact of IGF2 signaling on protein aggregation in models of Huntington's disease (HD) as proof of concept. Cell culture studies revealed that IGF2 treatment decreases the load of intracellular aggregates of mutant huntingtin and a polyglutamine peptide. These results were validated using induced pluripotent stem cells (iPSC)-derived medium spiny neurons from HD patients and spinocerebellar ataxia cases. The reduction in the levels of mutant huntingtin was associated with a decrease in the half-life of the intracellular protein. The decrease in the levels of abnormal protein aggregation triggered by IGF2 was independent of the activity of autophagy and the proteasome pathways, the two main routes for mutant huntingtin clearance. Conversely, IGF2 signaling enhanced the secretion of soluble mutant huntingtin species through exosomes and microvesicles involving changes in actin dynamics. Administration of IGF2 into the brain of HD mice using gene therapy led to a significant decrease in the levels of mutant huntingtin in three different animal models. Moreover, analysis of human postmortem brain tissue and blood samples from HD patients showed a reduction in IGF2 level. This study identifies IGF2 as a relevant factor deregulated in HD, operating as a disease modifier that buffers the accumulation of abnormal protein species
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