Shh SIGNALING INVOLVEMENT IN DEMYELINATION-REMYELINATION PROCESS

ALEJANDRA PAGANELLI; PATRICIA MATHIEU; PAULA FRANCO; ANA ADAMO

Buenos Aires

Congreso; LXII Reunión anual de la Sociedad Argentina de Investigación Clínica (SAIC); 2017

Shh SIGNALING INVOLVEMENT INDEMYELINATION-REMYELINATION PROCESS Multiple sclerosis (MS) isone of the  most common neurological disorders affecting youngpeople worldwide. MS is characterized by inflammation, and demyelination; inturn, spontaneous remyelination is driven by oligodendroglial precursor cells(OPCs) but is usually incomplete, as OPCs fail to mature into myelinatingoligodencrocytes (OLs), thus leading to neurodegeneration.Among several signalingpathways taking part in OPC maturation, Sonic hedgehog (Shh) has been recentlyshown to attenuate myelin damage through an increase in OPC number andmaturation in a focal demyelination model. The transduction of hedgehog signalingclassically involves transmembrane proteins Patched (Ptc) and Smoothened(Smo). In the absence of Shh ligand, downstream hedgehog signaling isrepressed, as Ptc suppresses Smo and inhibits the Gli transcription factors toact on target genes. This repression is relieved when Shh binds Ptc. In this context, the aim ofthis work was to study Shh signaling during demyelination and remyelination ina cuprizone (CPZ)-induced demyelination model in rats, and to further investigateShh protein as a potential biomarker of different stages of MS.After weaning, Wistar rats were fed a 0.6% CPZ diet for 2 weeks to trigger demyelination, later fed a control dietto allow remyelination, and sacrificed 7d before (-7d), upon (0d), and 7, 14and 21d (+7d, +14d and +21d) after CPZ withdrawal. Demyelination andremyelination were characterized through myelin basic protein (MBP)immunofluorescence (IF) at different times and the Shh pathway was analyzed by Western blot, q-PCR andIF along the process. Westernblot analyses showed an increase in precursor and cleaved Shh in the corpuscallosum of CPZ animals at -7d, 0d and +7d. q-PCR assays rendered an increasein Smo and Gli1 during remyelination. These preliminary resultssuggest stage-specific Shh signaling participation in demyelination andremyelination, and its potential use as a biomarker of MS stages.