Background: The mechanism by which astrocytes contribute to disease progression in mutant SOD1 mouse models of ALS is not known.Results: Mutant SOD1 astrocytes release mutant SOD1-containing exosomes that are toxic for motor neurons.Conclusion: Astrocyte-derived exosomes may have a role in disease spreading and motor neuron pathology.Significance: New therapeutic approaches should target exosomes to contain disease progression.
BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal progressive motor neuron disease, for which there are still no diagnostic/prognostic test and therapy. Specific molecular biomarkers are urgently needed to facilitate clinical studies and speed up the development of effective treatments.Methodology/Principal FindingsWe used a two-dimensional difference in gel electrophoresis approach to identify in easily accessible clinical samples, peripheral blood mononuclear cells (PBMC), a panel of protein biomarkers that are closely associated with ALS. Validations and a longitudinal study were performed by immunoassays on a selected number of proteins. The same proteins were also measured in PBMC and spinal cord of a G93A SOD1 transgenic rat model. We identified combinations of protein biomarkers that can distinguish, with high discriminatory power, ALS patients from healthy controls (98%), and from patients with neurological disorders that may resemble ALS (91%), between two levels of disease severity (90%), and a number of translational biomarkers, that link responses between human and animal model. We demonstrated that TDP-43, cyclophilin A and ERp57 associate with disease progression in a longitudinal study. Moreover, the protein profile changes detected in peripheral blood mononuclear cells of ALS patients are suggestive of possible intracellular pathogenic mechanisms such as endoplasmic reticulum stress, nitrative stress, disturbances in redox regulation and RNA processing.Conclusions/SignificanceOur results indicate that PBMC multiprotein biomarkers could contribute to determine amyotrophic lateral sclerosis diagnosis, differential diagnosis, disease severity and progression, and may help to elucidate pathogenic mechanisms.
The fertile period of women's life compared to menopause is associated with a lower incidence of degenerative inflammatory diseases. In brain, estrogens ameliorate brain performance and have positive effects on selected neural pathologies characterized by a strong inflammatory component. We thus hypothesized that the inflammatory response is a target of estrogen action; several studies including ours provided strong evidence to support this prediction. Microglia, the brain's inflammatory cells, and circulating monocytes express the estrogen receptors ER-alpha and ER-beta and their responsiveness in vivo and in vitro to pro-inflammatory agents, such as lipopolysaccharide (LPS), is controlled by 17beta-estradiol (E(2)). Susceptibility of central nervous system (CNS) macrophage cells to E(2) is also preserved in animal models of neuroinflammatory diseases, in which ER-alpha seems to be specifically involved. At the molecular level, induction of inflammatory gene expression is blocked by E(2). We recently observed that, differently from conventional anti-inflammatory drugs, E(2) stimulates a nongenomic event that interferes with the LPS signal transduction from the plasma membrane to cytoskeleton and intracellular effectors, which results in the inhibition of the nuclear translocation of NF-kappaB, a transcription factor of inflammatory genes. Interference with NF-kappaB intracellular trafficking is selectively mediated by ER-alpha. In summary, evidence from basic research strongly indicates that the use of estrogenic drugs that can mimic the anti-inflammatory activity of E(2) might trigger beneficial effects against neurodegeneration in addition to carrying out their specific therapeutic function.
Peptidylprolyl isomerase A (PPIA), also known as cyclophilin A, is a multifunctional protein with peptidyl-prolyl cis-trans isomerase activity. PPIA is also a translational biomarker for amyotrophic lateral sclerosis, and is enriched in aggregates isolated from amyotrophic lateral sclerosis and frontotemporal lobar degeneration patients. Its normal function in the central nervous system is unknown. Here we show that PPIA is a functional interacting partner of TARDBP (also known as TDP-43). PPIA regulates expression of known TARDBP RNA targets and is necessary for the assembly of TARDBP in heterogeneous nuclear ribonucleoprotein complexes. Our data suggest that perturbation of PPIA/TARDBP interaction causes 'TDP-43' pathology. Consistent with this model, we show that the PPIA/TARDBP interaction is impaired in several pathological conditions. Moreover, PPIA depletion induces TARDBP aggregation, downregulates HDAC6, ATG7 and VCP, and accelerates disease progression in the SOD1(G93A) mouse model of amyotrophic lateral sclerosis. Targeting the PPIA/TARDBP interaction may represent a novel therapeutic avenue for conditions involving TARDBP/TDP-43 pathology, such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration.
Conflict of interest: JPJ, CG, and SP are owners of US patent application no. 15/532,909 titled "TDP-43-binding polypeptides useful for the treatment of neurodegenerative diseases." JPJ is chief scientific officer of ImStar Therapeutics.
The basement membrane (BM) is a layer of specialized extracellular matrix that surrounds normal prostate glands and preserves tissue integrity. Lack or discontinuity of the BM is a prerequisite for tumor cell invasion into interstitial spaces, thus favoring metastasis. Therefore, BM maintenance represents a barrier against cancer development and progression. In the study, we show that miR-205 participates in a network involving DNp63a, which is essential for maintenance of the BM in prostate epithelium. At the molecular level, DNp63a is able to enhance miR-205 transcription by binding to its promoter, whereas the microRNA can post-transcriptionally limit the amount of DNp63a protein, mostly by affecting DNp63a proteasomal degradation rather than through a canonical miRNA/target interaction. Functionally, miR-205 is able to control the deposition of laminin-332 and its receptor integrin-b4. Hence, pathological loss of miR-205, as widely observed in prostate cancer, may favor tumorigenesis by creating discontinuities in the BM. Here we demonstrate that therapeutic replacement of miR-205 in prostate cancer (PCa) cells can restore BM deposition and 3D organization into normal-like acinar structures, thus hampering cancer progression. MicroRNAs (miRNAs) are short, non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. 1 By hybridizing to at least partially complementary regions on target mRNAs, miRNAs can induce mRNA degradation or translation inhibition, thus finely tuning protein expression in a variety of biological processes. 1 Consequently, aberrant miRNA expression and function have been linked to the pathogenesis of human diseases, including cancer, where specific miRNAs have been proven to act as oncogenes or tumor suppressors. 2 We previously showed that miR-205 is downregulated in prostate cancer (PCa) compared with adjacent non-neoplastic tissue. 3 This finding was then confirmed by several independent studies (reviewed in Gandellini et al. 4 ; Schaefer et al. 5 ), and miR-205 recognized as the best single miRNA able to correctly distinguish prostate tumor from normal tissue. 6 We also reported that miR-205 acts as a tumor suppressor in human prostate, as its reintroduction in PCa cells reverts epithelial-to-mesenchymal transition (EMT), 3 thus suggesting that miR-205 reduction may drive the progression toward a cell phenotype with enhanced invasive properties and favor metastasis. Accordingly, tumors from patients with lymph node dissemination show lower miR-205 expression than those from node-negative patients. 3 However, evidence of a downregulation of the miRNA in clinically localized carcinomas 4 suggests that loss of miR-205 in PCa may anticipate disease progression. To gain insight into this early loss of the miRNA and into the mechanisms of PCa development, we investigated the physiological role of miR-205 in normal prostate.Prostatic epithelium is characterized by three different cell layers: (i) an outer, androgen-independent basal layer, lying on a basement m...
Resistance to the growth-inhibitory action of retinoic acid (RA), the bioactive derivative of vitamin A, is common in human tumors. One form of RA resistance has been associated with silencing and hypermethylation of the retinoic acid receptor 2 gene (RAR2), an RA-regulated tumor suppressor gene. The presence of an epigenetically silent RAR2 correlates with lack of the RA receptor ␣ (RAR␣). Normally, RAR␣ regulates RAR2 transcription by mediating dynamic changes of RAR2 chromatin in the presence and absence of RA. Here we show that interfering with RA signal through RAR␣ (which was achieved by use of a dominantnegative RAR␣, by downregulation of RAR␣ by RNA interference, and by use of RAR␣ antagonists) induces an exacerbation of the repressed chromatin status of RAR2 and leads to RAR2 transcriptional silencing. Further, we demonstrate that RAR2 silencing causes resistance to the growth-inhibitory effect of RA. Apparently, RAR2 silencing can also occur in the absence of DNA methylation. Conversely, we demonstrate that restoration of RA signal at a silent RAR2 through RAR␣ leads to RAR2 reactivation. This report provides proof of principle that RAR2 silencing and RA resistance are consequent to an impaired integration of RA signal at RAR2 chromatin.
p63 is a transcription factor required for the development and maintenance of ectodermal tissues in general, and skin keratinocytes in particular. The identification of its target genes is fundamental for understanding the complex network of gene regulation governing the development of epithelia. We report a list of almost 1000 targets derived from ChIP on chip analysis on two platforms; all genes analyzed changed in expression during differentiation of human keratinocytes. Functional annotation highlighted unexpected GO terms enrichments and confirmed that genes involved in transcriptional regulation are the most significant. A detailed analysis of these transcriptional regulators in condition of perturbed p63 levels confirmed the role of p63 in the regulatory network. Rather than a rigid master-slave hierarchical model, our data indicate that p63 connects different hubs involved in the multiple specific functions of the skin.
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