Striatal infusion of glial conditioned medium diminishes huntingtin pathology in r6/1 mice.
Huntington's disease is a neurodegenerative disorder caused by an expansion of CAG repeats in the huntingtin gene which produces widespread neuronal and glial pathology. We here investigated the possible therapeutic role of glia or glial products in Huntington's disease using striatal glial conditioned medium (GCM) from fetus mice (E16) continuously infused for 15 and 30 days with osmotic minipumps into the left striatum of R6/1 mice. Animals infused with GCM had significantly less huntingtin inclusions in the ipsilateral cerebral cortex and in the ipsilateral and contralateral striata than mice infused with cerebrospinal fluid. The numbers of DARPP-32 and TH positive neurons were also greater in the ipsilateral but not contralateral striata and substantia nigra, respectively, suggesting a neuroprotective effect of GCM on efferent striatal and nigro-striatal dopamine neurons. GCM increases activity of the autophagic pathway, as shown by the reduction of autophagic substrate, p-62, and the augmentation of LC3 II, Beclin-1 and LAMP-2 protein levels, direct markers of autophagy, in GCM infused mice. GCM also increases BDNF levels. These results suggest that CGM should be further explored as a putative neuroprotective agent in Huntington's disease.
Department of Neurobiology, Hospital "Ramón y Cajal", Madrid, Spain ; CIBERNED, Madrid, Spain.
Juan
J
Perucho
Maria José
MJ
Casarejos
Ana
A
Gómez
Carolina
C
Ruíz
Maria Ángeles
MÁ
Fernández-Estevez
Maria Paz
MP
Muñoz
Justo García
JG
de Yébenes
Maria Ángeles
MÁ
Mena
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry*; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000235:genetics / Q000378:metabolism; D005838:Genotype; D006801:Humans; D006816:Huntington Disease / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D017072:Neostriatum / Q000187:drug effects / Q000378:metabolism; D009457:Neuroglia / Q000166:cytology*
D019208:Brain-Derived Neurotrophic Factor; D017077:Culture Media, Conditioned; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32