Abstract
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.
Highlights
Huntington’s disease (HD) is an inherited neurodegenerative disorder as a result of the expansion of a CAG trinucleotide repeat in the huntingtin gene (HTT)
The target striatal area for implantation of the cannula is shown in figure 1 A, an anesthetized mouse with an implanted cannula is shown in Figure 1 B, and one brain with the tract of the cannula in the cerebral cortex is shown in Figure 1 C and 1 D
There were no differences in the food and water ingestion or in the weight evolution between the animals infused with cerebrospinal fluid (CSF) or glial conditioned medium (GCM)
Summary
Huntington’s disease (HD) is an inherited neurodegenerative disorder as a result of the expansion of a CAG trinucleotide repeat in the huntingtin gene (HTT). Cognitive deficits and parkinsonian symptoms are frequent in patients with HD, suggesting involvement of other brain regions such as the cerebral cortex and the nigrostriatal pathways that have been found altered in neuropathological studies [2]. There is glial pathology in human patients with HD [3,4,5] and in animal models of this disease [6,7]. Mutant HTT is expressed in glial cells and affects directly the neuron pathology in HD [8]. Htt inclusions are much more common in neurons than in glia in mutant mouse brains [9,10], suggesting that glial cells have mechanisms that prevent the accumulation and deposition of htt aggregates in glia
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