Humanin gene expression in fibroblast of Down syndrome subjects.

Down syndrome (DS) is characterized by trisomy of chromosome 21 and peculiar phenotype. Humanin (HN) is a mitochondrial short 24-residue polypeptide whit anti-apoptotic and neuroprotective effects. In this study we evaluated HN protein expression and HN mRNA levels in cultured fibroblasts from DS patients and normal controls. Our results obtained by immunocytochemistry, western-blot and qRT-PCR analysis show a significant HN up-regulation in DS patients. These results confirm previous studies and suggest a role for HN may in the DS phenotype.

Carnosine Prevents Aß-Induced Oxidative Stress and Inflammation in Microglial Cells: A Key Role of TGF-ß1.

Carnosine (ß-alanyl-L-histidine), a dipeptide, is an endogenous antioxidant widely distributed in excitable tissues like muscles and the brain. Carnosine is involved in cellular defense mechanisms against oxidative stress, including the inhibition of amyloid-beta (Aß) aggregation and the scavenging of reactive species. Microglia play a central role in the pathogenesis of Alzheimer's disease, promoting neuroinflammation through the secretion of inflammatory mediators and free radicals. However, the effects of carnosine on microglial cells and neuroinflammation are not well understood. In the present work, carnosine was tested for its ability to protect BV-2 microglial cells against oligomeric Aß1-42-induced oxidative stress and inflammation. Carnosine prevented cell death in BV-2 cells challenged with Aß oligomers through multiple mechanisms. Specifically, carnosine lowered the oxidative stress by decreasing NO and O2-• intracellular levels as well as the expression of iNOS and Nox enzymes. Carnosine also decreased the secretion of pro-inflammatory cytokines such as IL-1ß, simultaneously rescuing IL-10 levels and increasing the expression and the release of TGF-ß1. Carnosine also prevented Aß-induced neurodegeneration in mixed neuronal cultures challenged with Aß oligomers, and these neuroprotective effects were completely abolished by SB431542, a selective inhibitor of the type-1 TGF-ß receptor. Our data suggest a multimodal mechanism of action of carnosine underlying its protective effects on microglial cells against Aß toxicity with a key role of TGF-ß1 in mediating these protective effects.

A polymorphism (rs1042522) in TP53 gene is a risk factor for Down Syndrome in Sicilian mothers.

OBJECTIVE: Trisomy 21 is the most frequent genetic cause of intellectual disability. Tumor Protein 53 (TP53) gene down-regulation triggers chromosomal instability. A TP53 gene polymorphism c.215G > C (rs1042522) is associated with accumulation of aneuploid cells. We analyzed the TP53 c.215G > C (rs1042522) polymorphism in Sicilian mothers of subjects with Down Syndrome (DS) within a case-control study. METHODS: Nucleotide polymorphism was detected by pyrosequencing technology. RESULTS: The distribution of TP53 c.215G > C polymorphism showed significant difference between mothers of subjects with DS and controls. CONCLUSIONS: Our data show that TP53 c.215G > C polymorphism is a risk factor for DS in Sicilian mothers.

The in cis T251I and P587L POLG1 base changes: description of a new family and literature review.

Mutations in the polymerase gamma-1 (POLG1) gene, encoding the catalytic subunit of the mtDNA-specific polymerase-γ, compromise the stability of mitochondrial DNA (mtDNA) and are responsible for numerous clinical presentations as autosomal dominant or recessive progressive external ophthalmoplegia (PEO), sensory ataxia, neuropathy, dysarthria and ophthalmoparesis (SANDO), spinocerebellar ataxia with epilepsy (SCAE) and Alpers syndrome. POLG1 mutations result in extremely heterogeneous phenotypes which often have overlapping clinical findings, making it difficult to categorize patients into syndromes, and genotype-phenotype correlations are still unclear. We describe a new family with a particular spectrum of clinical signs, that carried the c.752C>T mutation in exon 3 (T251I) and the c.1760C>T in exon 10 (P587L) in cis. These mutations were associated in the proband and in her brother with the new probably pathogenic mutation c.347C>A in exon 2 (P116Q). The proband presented a progressive cognitive impairment, mild myopathy, dilated cardiac right atrium and posterior white matter mild signal alteration, while her brother had migraine, mild myopathy, palpebral ptosis and posterior white matter mild signal alteration. Their mother and their sister carried the in cis T251I and the P587L mutations. The first presented neurosensorial hypoacusia, fatigue, heart block and a cerebral arteriovenous malformation nidus, while the latter had borderline intellectual functioning and signs of muscular involvement. Their father, with the P116Q mutation, had diabetes and myopathy. The complexity of the genotype-phenotype correlations associated with POLG1 mutations is reinforced in this work as evidenced by the presence of different clinic features in patients carrying the same mutations.