L25 Trehalose rescues glial cell dysfunction in striatal cultures from HD R6/1 mice at early postnatal development

Background

Huntington’s disease (HD) is characterised by selective loss of striatal spiny neurons and intracellular inclusions of mutant huntingtin (mHTT) in neurons and glia. The role of glia in HD is not clear and has been considered secondary to neuronal damage.

Aims

We investigated early postnatal features of glia and the effects of trehalose, a disaccharide with antioxidant and autophagy promoting properties in models of HD.

Methods

We investigated abnormalities of early postnatal striatal glia of R6/1 mice (HD glia), at baseline and under epoxomicin stress and the protective effects of trehalose. We measured the survival and proliferation of cells, the production of free radicals, neurotrophic factors, the deposition of huntingtin+ and synuclein+ inclusions, the markers of macro autophagy and chaperone-mediated autophagy and proteosomal function and the markers of mitochondrial activity. The statistical analysis was performed with one-way ANOVA and Newman Keuls tests. Interactions between genotype and treatment were analysed by two-way ANOVA and Bonferroni post-test. Differences were significant when p < 0.05.

Results

HD glia is abnormal at 20 days postnatal. It has more reactive astrocytes and increased expression of GFAP but with less replication capacity, less A2B5+ glial progenitors and more microglia. HD glia has less GSH and it is more susceptible to H2O2 and epoxomicin. Expression GDNF and BDNF is reduced, function of UPS and the autophagy is abnormal. Treatment of HD glia with trehalose enhances autophagy, inhibits p62/SQSTM1 accumulation and facilitates the degradation of cytoplasmic aggregates of mHTT and α-synuclein. Trehalose reduces microglia activation, reverses the disrupted cytoskeleton of astrocytes and increases their replication. Trehalose up-regulates mature-BDNF expression and secretion.

Conclusion

HD glia suffers early changes which may contribute to HD pathology. Trehalose could be a very promising compound for treatment of HD.