ABSTRACT
In hereditary Huntington's disease, a triplet repeat disease, there is extensive loss of striatal neurons. It has been shown that brain-derived neurotrophic factor (BDNF) protects striatal neurons against a variety of insults. We confirmed that BDNF enhances survival and DARPP-32 expression in primary striatal cultures derived from postnatal mice. Furthermore, BDNF inhibited intracellular oxyradical stress triggered by dopamine, and partially blocked basal and dopamine-induced apoptosis. Nevertheless, BDNF failed to rescue striatal neurons from dopamine-induced cell death. Therefore, BDNF inhibits free radical and apoptotic pathways in medium spiny neurons, but does so downstream from the point of commitment to cell death.
Subject(s)
Apoptosis/drug effects , Brain-Derived Neurotrophic Factor/pharmacology , Corpus Striatum/cytology , Dopamine/pharmacology , Nerve Tissue Proteins , Neurons/drug effects , Animals , Autophagy , Cell Survival/drug effects , Cells, Cultured , Dopamine and cAMP-Regulated Phosphoprotein 32 , Enzyme Inhibitors/pharmacology , Free Radicals/metabolism , Huntington Disease/genetics , Huntington Disease/pathology , Mice , Mice, Inbred C57BL , Neurons/cytology , Neurons/metabolism , Oxidative Stress/physiology , Phosphoproteins/pharmacology , Trinucleotide RepeatsABSTRACT
Huntington's disease (HD) is caused by an expanded CAG repeat in exon 1 of the gene coding for the huntingtin protein. The cellular pathway by which this mutation induces HD remains unknown, although alterations in protein degradation are involved. To study intrinsic cellular mechanisms linked to the mutation, we examined dissociated postnatally derived cultures of striatal neurons from transgenic mice expressing exon 1 of the human HD gene carrying a CAG repeat expansion. While there was no difference in cell death between wild-type and mutant littermate-derived cultures, the mutant striatal neurons exhibited elevated cell death following a single exposure to a neurotoxic concentration of dopamine. The mutant neurons exposed to dopamine also exhibited lysosome-associated responses including induction of autophagic granules and electron-dense lysosomes. The autophagic/lysosomal compartments co-localized with high levels of oxygen radicals in living neurons, and ubiquitin. The results suggest that the combination of mutant huntingtin and a source of oxyradical stress (provided in this case by dopamine) induces autophagy and may underlie the selective cell death characteristic of HD.
