111,917 research outputs found
The role of the HSPB8-BAG3 complex in age-related protein misfolding diseases
No full textBackground and Purpose - The aggregation of misfolded, mutated proteins (SOD1, TDP-43) is a pathological hallmark of the familial forms of Amyotrophic Lateral Sclerosis (ALS). Cells have evolved an elaborate protein quality control system mediated by molecular chaperones, in order to facilitate folding/refolding of these misfolded species that can exert neurotoxicity. When folding is unsuccessful, chaperones can also target the misfolded proteins for degradation, thereby preventing protein aggregation. Intracellular degradation is primarily mediated by two proteolytic systems: the ubiquitin proteasome system and autophagy [1], and a proper balance and cross-talk between them is required for normal protein homeostasis, while their alteration may contribute to ageing and disease [2,3].
We already published that overexpression of the small heat shock protein HSPB8 (and its partner Bag3) in motoneuron cells (NSC34) prevents aggregation of mutated SOD1 and TDP-43, by either directly targeting them to the autophagic vacuoles for degradation and/or restoring/boosting the autophagy flux [4,5]. Moreover our recent data indicate that BAG3 upregulation, following proteasome inhibition, significantly contributes to the compensatory activation of autophagy and to the re-routing of (poly)ubiquitinated proteins to autophagy for degradation. Motoneurons are particularly sensitive to misfolded protein toxicity, but also other cell types could be affected. As an example, muscle-restricted expression of the mutSOD1, results in muscle atrophy associated with motoneuron death.
Methods and Results - We compared the potential mutSOD1 toxicity in motoneuron (NSC34) and muscle (C2C12) cells, and found that muscle ALS models possess much higher proteasome activity and autophagic power than motoneuron ALS models, which allow to better cope with misfolded protein aggregation [6]. The same results were also obtained with mutTDP43. These findings were further confirmed analyzing the expression of the LC3 and p62 genes (two well known autophagic markers) as well as of BAG3 and HSPB8 genes, which after proteasome inhibition are all higher activated in muscle cells than motoneuron cells. Finally we also found that the knock-down of HSPB8 increases the aggregation of both wt and mutTDP43 in C2C12, but only of mutTDP43 in NSC34, suggesting that HSPB8 plays a primary role in TDP43 turn-over especially in muscle cells.
Conclusions - These data together with the observation that HSPB8 and BAG3 are upregulated in muscles of ALS transgenic mice only at symptomatic stage and that HSPB8 is upregulated in surviving motor neurons in transgenic ALS mice during disease progression, strongly suggest that the boosting of this complex may serve to clear aggregates in chronic neurodegenerative diseases.
References
[1] Rubinsztein DC. 2006. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature 443:780-786.
[2] Gamerdinger M, Hajieva P, Kaya AM, Wolfrum U, Hartl FU, Behl C. 2009. Protein quality control during aging involves recruitment of the macroautophagy pathway by BAG3. Embo J 28:889-901.
[3] Morimoto RI. 2008. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev 22:1427-1438.
[4] Crippa V, Sau D, Rusmini P, Boncoraglio A, Onesto E, Bolzoni E, Galbiati M, Fontana E, Marino M, Carra S, Bendotti C, De Biasi S, Poletti A. 2010. The small heat shock protein B8 (HspB8) promotes autophagic removal of misfolded proteins involved in amyotrophic lateral sclerosis (ALS). Human molecular genetics 19:3440-3456.
[5] Carra S, Crippa V, Rusmini P, Boncoraglio A, Minoia M, Giorgetti E, Kampinga HH, Poletti A. 2011. Alteration of protein folding and degradation in motor neuron diseases: Implications and protective functions of small heat shock proteins. Prog Neurobiol 97:83-100.
[6] Onesto E, Rusmini P, Crippa V, Ferri N, Zito A, Galbiati M, Poletti A. 2011. Muscle cells and motoneurons differentially remove mutant SOD1 causing familial amyotrophic lateral sclerosis. Journal of Neurochemistry 118: 266–280
Amyotrophic lateral sclerosis: SOD1 mutants and impairmeht of ubiquitin proteasome pathway
No full textSelf-assembling peptides: From design to biomedical applications
No full textSelf-assembling peptides could be considered a novel class of agents able to harvest an array of micro/nanostructures that are highly attractive in the biomedical field. By modifying their amino acid composition, it is possible to mime several biological functions; when assembled in micro/nanostructures, they can be used for a variety of purposes such as tissue regeneration and engineering or drug delivery to improve drug release and/or stability and to reduce side effects. Other significant advantages of self-assembled peptides involve their biocompatibility and their ability to efficiently target molecular recognition sites. Due to their intrinsic characteristics, self-assembled peptide micro/nanostructures are capable to load both hydrophobic and hydrophilic drugs, and they are suitable to achieve a triggered drug delivery at disease sites by inserting in their structure’s stimuli-responsive moieties. The focus of this review was to summarize the most recent and significant studies on self-assembled peptides with an emphasis on their application in the biomedical field
Different behaviour of mutant SOD1 in motorneuronal and muscle cellular models of Amyotrophic Lateral Sclerosis
No full textThe effect of connectivity on information in neural networks
No full textA mathematical model quantifies the amount of information/exchanged in neural networks as a function of network connectivityQ.</p
Relating the small world coefficient to the entropy of 2D networks and applications in neuromorphic engineering
No full textThe study of networks pervades science. The techniques of networks are recently being applied to
biomedical disciplines, where the complexity of biomedical systems requires new schemes that can
process elevated volumes of data with high efficiency. Artificial neural networks, on which much of
artificial intelligence relies, are statistical models partially modeled on biological neural networks.
They are capable of modeling and processing nonlinear relationships between inputs and outputs in
parallel—in opposition to deterministic models and classical computation schemes, which perform
tasks in linear sequences of calculations and may fail to keep up with the challenges of complex
biological systems. For these biological or bio-inspired systems, the performance of the networks
depends on their topological characteristics. Here, we generated a large number of configurations of
points in a plane, in which the entropy s of the configurations was varied over large intervals. Then, we
connected points using the Waxman model to obtain the corresponding networks. In correlating the
entropy (s) to the small-world coefficient (SW) of those networks, we found thatSWvaries
hyperbolically with s asSW=0.88+0.28/s, where s is expressed in millibits per node. Since the
entropy of a distribution of points depends in turn on the density of those points in the plane, such a
relationship suggests that the distribution of mass (s) in a complex system determines the topological
characteristics (SW) of that system. The small-world-ness of the system, in turn, determines its
information efficiency. These findings may have implications in neuromorphic engineering, where
chips modeled on biological brains may lead to machines that are able, as for some examples, to
diagnose diseases, develop drugs and drug delivery systems faster, design personalized treatments
targeted to patient’s needs
Small-world networks of neuroblastoma cells cultured in three-dimensional polymeric scaffolds featuring multi-scale roughness
No full textUnderstanding the mechanisms underlying cell-surface interaction is of fundamental importance for the rational design of scaffolds aiming at tissue engineering, tissue repair and neural regeneration applications. Here, we examined patterns of neuroblastoma cells cultured in three-dimensional polymeric scaffolds obtained by two-photon lithography. Because of the intrinsic resolution of the technique, the micrometric cylinders composing the scaffold have a lateral step size of ~200 nm, a surface roughness of around 20 nm, and large values of fractal dimension approaching 2.7. We found that cells in the scaffold assemble into separate groups with many elements per group. After cell wiring, we found that resulting networks exhibit high clustering, small path lengths, and small-world characteristics. These values of the topological characteristics of the network can potentially enhance the quality, quantity and density of information transported in the network compared to equivalent random graphs of the same size. This is one of the first direct observations of cells developing into 3D small-world networks in an artificial matrix
Protein aggregation and proteasome impairment in motorneuronal and muscle cellular models of Amyotrophic Lateral Sclerosis
No full textEffetto dell’espansione del tratto poliglutamminico del recettore degli androgeni sul differenziamento dei motoneuroni
No full textInter-species differences in regulation of the progranulin–sortilin axis in TDP-43 cell models of neurodegeneration
No full textCytoplasmic aggregates and nuclear depletion of the ubiquitous RNA-binding protein TDP-43 have been described in the autoptic brain tissues of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTLD) patients and both TDP-43 loss-of-function and gain-of-function mechanisms seem to contribute to the neurodegenerative process. Among the wide array of RNA targets, TDP-43 regulates progranulin (GRN) mRNA stability and sortilin (SORT1) splicing. Progranulin is a secreted neurotrophic and neuro-immunomodulatory factor whose endocytosis and delivery to the lysosomes are regulated by the neuronal receptor sortilin. Moreover, GRN loss-of-function mutations are causative of a subset of FTLD cases showing TDP-43 pathological aggregates. Here we show that TDP-43 loss-of-function differently affects the progranulin–sortilin axis in murine and human neuronal cell models. We demonstrated that although TDP-43 binding to GRN mRNA occurs similarly in human and murine cells, upon TDP-43 depletion, a different control of sortilin splicing and protein content may determine changes in extracellular progranulin uptake that account for increased or unchanged secreted protein in murine and human cells, respectively. As targeting the progranulin–sortilin axis has been proposed as a therapeutic approach for GRN-FTLD patients, the inter-species differences in TDP-43-mediated regulation of this pathway must be considered when translating studies from animal models to patients
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