Background: Early onset dementias (EOD) are rare neurodegenerative dementias that present before 65 years. Genetic factors have a substantially higher pathogenetic contribution in EOD patients than in late onset dementia. Objective: To identify known and/or novel rare variants in major candidate genes associated to EOD by high-throughput sequencing. Common-risk variants of apolipoprotein E ( APOE ) and prion protein ( PRNP ) genes were also assessed. Methods: We studied 22 EOD patients recruited in Memory Clinics, in the context of studies investigating genetic forms of dementia. Two methodological approaches were applied for the target-Next Generation Sequencing (NGS) analysis of these patients. In addition, we performed progranulin plasma dosage, C9Orf72 hexanucleotide repeat expansion analysis, and APOE genotyping. Results: We detected three rare known pathogenic mutations in the GRN and PSEN2 genes and eleven unknown-impact mutations in the GRN , VCP , MAPT , FUS, TREM2, and NOTCH3 genes. Six patients were carriers of only common risk variants ( APOE and PRNP ), and one did not show any risk mutation/variant. Overall, 69% ( n = 9) of our early onset Alzheimer’s disease (EAOD) patients, compared with 34% ( n = 13) of sporadic late onset Alzheimer’s disease (LOAD) patients and 27% ( n = 73) of non-affected controls (ADNI, whole genome data), were carriers of at least two rare/common risk variants in the analyzed candidate genes panel, excluding the full penetrant mutations. Conclusion: This study suggests that EOD patients without full penetrant mutations are characterized by higher probability to carry polygenic risk alleles that patients with LOAD forms. This finding is in line with recently reported evidence, thus suggesting that the genetic risk factors identified in LOAD might modulate the risk also in EOAD.
Huntington's disease is an inherited disorder caused by expanded stretch of consecutive trinucleotides (cytosine-adenosine-guanine, CAG) within the first exon of the huntingtin (HTT) gene on chromosome 4 (p16.3). The mutated huntingtin (mHTT) gains toxic function, probably through mechanisms that involve aberrant interactions in several pathways, causing cytotoxicity. Pathophysiology of disease involves several tissues; indeed it has been shown that there is a broad toxic effect of mHTT in the peripheral tissue of patients with HD, not only in the central nervous system. In this study we compared gene expression profiles (GEP) of HD fibroblasts and matched controls using microarray technology. We used RT-PCR to test the consistency of the microarray data and we found four genes up-regulated in HD patients with respect to control individuals. The genes appear to be involved in different pathways that have been shown to be perturbed even in HD models and patients. Although our study is preliminary and has to be extended to a larger cohort of HD patients and controls, nevertheless it shows that gene expression profiles seem to be altered in the fibroblasts of HD patients. Validation of the differential expressions at the protein level is required to ascertain if this cell type can be considered a suitable model for the identification of HD biomarkers.
Fibronectin (FN) is an extracellular matrix (ECM)pro Fibronectin (FN)1 is an adhesive heterodimeric glycoprotein present in the extracellular matrix (ECM) of connective tissues in disulfide cross-linked insoluble fibrils and in the blood in dimeric soluble form. FN contains three types of homologous repeats (I-III), organized in functional domains, connected by flexible, protease-sensitive segments, which allow the binding of the molecule to ECM components (fibrin, heparin, collagen, FN, and integrin receptors) (1-3). Through these multiple interactions, FN provides a scaffold for ECM assembly and takes part in different physiological and pathological processes (4 -7).One of the earliest observations concerning FN was that in vitro transformed and tumor-derived cells often fail to deposit a matrix, whereas the normal counterparts do have a matrix (8, 9). Because addition of FN to tumor-derived cultured cells improves cell adhesion and induces ECM and cytoskeleton organization, supporting the normal cell morphology, FN has been associated with the normal cell phenotypes (6, 10, 11). The inability of the transformed cells to deposit the ECM has been related to the proteolytic fragmentation of FN generated by the enhanced levels of proteases released by tumors and transformed cells (12)(13)(14), as well as to the down-regulation of the expression of integrin receptors binding to FN and supporting ECM assembly (7). Along these lines are also observations that an excessive ECM, containing collagens and FN, i.e. desmoplasia, is often deposited in stroma surrounding invasive carcinomas (15). It has been proposed that this stromal response temporarily antagonizes tumor growth and invasion (14, 16). Thus, the absence of an ECM of FN is associated with the transformed phenotype, whereas the presence of the ECM restricts cell invasion and migration in many tumor cells. The transition from assembly to nonassembly of the ECM may therefore be an important stage in cancer progression.The assembly of FN into fibrils in vitro and in vivo requires multiple binding sites within FN including an N-terminal region consisting of the first five type I repeats (17-21), the RGD cell-binding site (22-23), the synergistic cell adhesive regions (24 -25), the I 12 repeat involved in the stabilization of FN fibrils (26), and a site located at or near the junction of type I 9 and type III 1 repeats (27-28). In addition, an FN-FN-binding site has been identified in a 14-kDa FNfg containing the first two type III repeats (29). A 76-amino acid FN peptide, including this site, corresponding to a C-portion of the type-III 1 repeat, has been shown to convert FN into a polymeric fibrillar form called superfibronectin (sFN) (29). sFN resembles the matrix fibrils produced by cultured fibroblasts, is highly adhesive, can inhibit cell spreading and migration in vitro, prevents tumor formation in nude mice injected with human tumorigenic cells, and has a strong antimetastatic activity (30). Recently, the
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