PINK1-induced mitophagy promotes neuroprotection in Huntington's disease.

Huntington's disease (HD) is a fatal neurodegenerative disorder caused by aberrant expansion of CAG repeat in the huntingtin gene. Mutant Huntingtin (mHtt) alters multiple cellular processes, leading to neuronal dysfunction and death. Among those alterations, impaired mitochondrial metabolism seems to have a major role in HD pathogenesis. In this study, we used the Drosophila model system to further investigate the role of mitochondrial damages in HD. We first analyzed the impact of mHtt on mitochondrial morphology, and surprisingly, we revealed the formation of abnormal ring-shaped mitochondria in photoreceptor neurons. Because such mitochondrial spheroids were previously detected in cells where mitophagy is blocked, we analyzed the effect of PTEN-induced putative kinase 1 (PINK1), which controls Parkin-mediated mitophagy. Consistently, we found that PINK1 overexpression alleviated mitochondrial spheroid formation in HD flies. More importantly, PINK1 ameliorated ATP levels, neuronal integrity and adult fly survival, demonstrating that PINK1 counteracts the neurotoxicity of mHtt. This neuroprotection was Parkin-dependent and required mitochondrial outer membrane proteins, mitofusin and the voltage-dependent anion channel. Consistent with our observations in flies, we demonstrated that the removal of defective mitochondria was impaired in HD striatal cells derived from HdhQ111 knock-in mice, and that overexpressing PINK1 in these cells partially restored mitophagy. The presence of mHtt did not affect Parkin-mediated mitochondrial ubiquitination but decreased the targeting of mitochondria to autophagosomes. Altogether, our findings suggest that mitophagy is altered in the presence of mHtt and that increasing PINK1/Parkin mitochondrial quality control pathway may improve mitochondrial integrity and neuroprotection in HD.

A role for nitric oxide in sensory-induced neurogenesis in an adult insect brain.

In the adult cricket, neurogenesis occurs in the mushroom bodies, the main integrative structures of the insect brain. Mushroom body neuroblast proliferation is modulated in response to environmental stimuli. However, the mechanisms underlying these effects remain unspecified. In the present study, we demonstrate that electrical stimulation of the antennal nerve mimics the effects of olfactory activation and increases mushroom body neurogenesis. The putative role of nitric oxide (NO) in this activity-regulated neurogenesis was then explored. In vivo and in vitro experiments demonstrate that NO synthase inhibition decreases, and NO donor application stimulates neuroblast proliferation. NADPH-d activity, anti-L-citrulline immunoreactivity, as well as in situ hybridization with a probe specific for Acheta NO synthase were used to localize NO-producing cells. Combining these three approaches we clearly establish that mushroom body interneurons synthesize NO. Furthermore, we demonstrate that experimental interventions known to upregulate neuroblast proliferation modulate NO production: rearing crickets in an enriched sensory environment induces an upregulation of Acheta NO synthase mRNA, and unilateral electrical stimulation of the antennal nerve results in increased L-citrulline immunoreactivity in the corresponding mushroom body. The present study demonstrates that neural activity modulates progenitor cell proliferation and regulates NO production in brain structures where neurogenesis occurs in the adult insect. Our results also demonstrate the stimulatory effect of NO on mushroom body neuroblast proliferation. Altogether, these data strongly suggest a key role for NO in environmentally induced neurogenesis.

Influence of environmental stimulation on neurogenesis in the adult insect brain.

Mushroom bodies are the main integrative structures of insect brain. They receive sensory information from the eyes, the palps, and the antennae. In the house cricket, Acheta domesticus, a cluster of mushroom body neuroblasts keeps producing new interneurons during an insect's life span. The aim of the present work is to study the impact of environmental stimuli on mushroom body neurogenesis during adulthood. Crickets were reared either in an enriched environment, where they received complex environmental and congeneric stimulations or isolated in small cages and deprived of most visual, auditory, and olfactory stimuli. They then were injected with a S-phase marker, 5-bromo, 2'-deoxyuridine (BrdU) and sacrificed at different periods of their life. Neurogenesis and cell survival were estimated by counting the number of BrdU-labeled cells in the mushroom bodies. Environmentally enriched crickets were found to have an increased number of newborn cells in their mushroom bodies compared with crickets housed in cages with an impoverished environment. This effect of external factors on neurogenesis seems to be limited to the beginning of imaginal life. Furthermore, no cell loss could be detected among the newborn neurons in either environmental situation, suggesting that cell survival was not affected by the quality of the environment. Considering vertebrate studies which showed that enriched environment increases hippocampal cell survival and improves animal performances in spatial learning tests, we suggest that the increased number of interneurons produced in an integrative brain structure after exposure to enriched environment could contribute to adaptive behavioral performances in adult insects.