Leprosy piRnome: exploring new possibilities for an old disease.

Leprosy, which is caused by the human pathogen Mycobacterium leprae, causes nerve damage, deformity and disability in over 200,000 people every year. Because of the long doubling time of M. leprae (13 days) and the delayed onset of detectable symptoms, which is estimated to be approximately 3-7 years after infection, there is always a large percentage of subclinically infected individuals in the population who will eventually develop the disease, mainly in endemic countries. piRNAs comprise the largest group of small noncoding RNAs found in humans, and they are distinct from microRNAs (miRNAs) and small interfering RNAs (siRNAs). piRNAs function in transposon silencing, epigenetic regulation, and germline development. The functional role of piRNAs and their associated PIWI proteins have started to emerge in the development of human cancers and viral infections, but their relevance to bacterial diseases has not been investigated. The present study reports the piRNome of human skin, revealing that all but one of the piRNAs examined are downregulated in leprosy skin lesions. Considering that one of the best characterized functions of piRNAs in humans is posttranscriptional mRNA silencing, their functions are similar to what we have described for miRNAs, including acting on apoptosis, M. leprae recognition and engulfment, Schwann cell (SC) demyelination, epithelial-mesenchymal transition (EMT), loss of sensation and neuropathic pain. In addition to new findings on leprosy physiopathology, the discovery of relevant piRNAs involved in disease processes in human skin may provide new clues for therapeutic targets, specifically to control nerve damage, a prominent feature of leprosy that has no currently available pharmaceutical treatment.

Current Non-viral siRNA Delivery Systems as a Promising Treatment of Skin Diseases.

BACKGROUND: Gene therapy is a new approach to discover and treat many diseases. It has attracted considerable attention from researchers in the last decades. The gene therapy through RNA interference has been considered one of the most recent and revolutionary approaches used in individualized therapy. In the last years, we have witnessed the rapid development in the field of the gene silencing and knockdown by topical siRNA. Its application in gene therapy has become an attractive alternative for drug development. METHODS: This article will address topical delivery of siRNA as a promising treatment for skin disorders. An update on the advances in siRNA-based nanocarriers as a powerful therapeutic strategy for several skin diseases will be discussed giving emphasis on in vitro evaluations. RESULTS: Through the in-depth review of the literature on the use of siRNAs for skin diseases we realize how widespread this use is. We have also realized that nanoparticles as non-viral vectors are increasingly being explored. Skin diseases where the use of siRNA has been explored most are skin cancer (melanoma and nonmelanoma), psoriasis, vitiligo, dermatitis and leprosy. But we also report here other diseases where the use of siRNA has been growing as acne, alopecia areata, cutaneous leishmaniasis, mycoses, herpes, epidermolysis bullosa and oculocutaneous albinism. Also highlighted, the first clinical trial of siRNA for cutaneous diseases, aimed at Pathyounychia Congenita. CONCLUSION: The treatment of skin diseases based on topical delivery of siRNA, which act by inhibiting the expression of target transcripts, offers many potential therapeutic advantages for suppressing genes into the skin.

TMP21 regulates Abeta production but does not affect caspase-3, p53, and neprilysin.

The presenilin (PS)-dependent gamma-secretase activity refers to a high molecular mass-complex including, besides PS1 or PS2, three other proteins recently identified, namely nicastrin, Aph-1, and Pen-2. This proteolytic complex has been shown to contribute to both gamma- and epsilon-cleavages of the beta-amyloid precursor protein (betaAPP), thereby generating beta-amyloid peptides (Abeta) and the APP intracellular domain (AICD), respectively. TMP21, a member of the p24 cargo protein family, was recently shown to interact with PS complexes. Interestingly, TMP21 modulates gamma-secretase-mediated Abeta production but does not regulate epsilon-secretase-derived AICD formation [F. Chen, H. Hasegawa, G. Schmitt-ulms, T. Kawarai, C. Bohm, T. Katayama, Y. Gu, N. Sanjo, M. Glista, E. Rogaeva, Y. Wakutami, R. Pardossi-Piquard, X. Ruan, A. Tandon, F. Checler, P. Marambaud, K. Hansen, D. Westaway, P. St. George-Hyslop, P. Fraser, TMP21 is a presenilin complex component that modulates gamma- but not epsilon-secretase activities, Nature 440 (2006) 1208-1212]. Here we investigate the functional incidence of the over-expression or depletion of TMP21 on both intracellular and secreted Abeta recoveries and AICD-associated phenotypes. First we confirm that TMP21 depletion yields increased levels of secreted Abeta40. However, we demonstrate that both staurosporine-stimulated caspase-3 activation, p53 and neprilysin expression and activity were not affected by TMP21 over-expression or depletion. Overall, our functional data further reinforce the view that TMP21 behaves as a regulator of gamma- but not epsilon-cleavages generated by PS-dependent gamma-secretase complex.