Altered lipid metabolism in a Drosophila model of Friedreich's ataxia

Abstract

Friedreich's ataxia (FRDA) is the most common form of autosomal recessive ataxia caused by a deficit in the mitochondrial protein frataxin. Although demyelination is a common symptom in FRDA patients, no multicellular model has yet been developed to study the involvement of glial cells in FRDA. Using the recently established RNAi lines for targeted suppression of frataxin in Drosophila, we were able to study the effects of general versus glial-specific frataxin downregulation. In particular, we wanted to study the interplay between lowered frataxin content, lipid accumulation and peroxidation and the consequences of these effects on the sensitivity to oxidative stress and fly fitness. Interestingly, ubiquitous frataxin reduction leads to an increase in fatty acids catalyzing an enhancement of lipid peroxidation levels, elevating the intracellular toxic potential. Specific loss of frataxin in glial cells triggers a similar phenotype which can be visualized by accumulating lipid droplets in glial cells. This phenotype is associated with a reduced lifespan, an increased sensitivity to oxidative insult, neurodegenerative effects and a serious impairment of locomotor activity. These symptoms fit very well with our observation of an increase in intracellular toxicity by lipid peroxides. Interestingly, co-expression of a Drosophila apolipoprotein D ortholog (glial lazarillo) has a strong protective effect in our frataxin models, mainly by controlling the level of lipid peroxidation. Our results clearly support a strong involvement of glial cells and lipid peroxidation in the generation of FRDA-like symptoms.

Bone marrow transplantation stimulates neural repair in Friedreich's ataxia mice

“…Both dysfunctional frataxin‐deficient neurons and glia are likely to contribute to neuropathology in FA 6, 7. Pathology in FA occurs primarily in the DRG, with significant but independent changes to both the large sensory neurons and surrounding satellite cells, ultimately resulting in neuronal atrophy 5.…”

Mitoferrin modulates iron toxicity in a Drosophila model of Friedreich׳s ataxia

“…It is important to note that only fhRNAi-2 facilitates a ubiquitous frataxin reduction compatible with high adult eclosion rates. On the contrary, fhRNAi-1 triggers developmental lethality with general drivers but it is an excellent tool for analyzing frataxin depletion in a tissue-specific manner [37][38][39]. All experiments were done at room temperature.…”

“…The absence of such evidence prompted us to assess the neuroprotective abilities of genetic manipulation of iron storage and transport in the nervous system of flies displaying frataxin downregulation. We have previously reported a critical role for glial cells in the FRDA pathogenesis [38]. Among other effects, glia-specific frataxin depletion triggered locomotor dysfunction and an age-dependent brain vacuolization [38].…”

“…The Drosophila model of FRDA generated by our group and collaborators ( [36], fhRNAi-2) displays a systemic and moderate reduction of frataxin expression of approximately 70%; a reduction akin to that observed in patients [44,45]. The remaining 30% frataxin is sufficient to bypass any developmental lethality, to facilitate normal aconitase or complex II activities, to induce a strong sensitivity against oxidative insult and to increase the production of lipid peroxides [36,38].…”

Lipid metabolism in <italic>Drosophila</italic>: development and disease

“…Interestingly, ApoD has a strong protective effect in this model as well. Therefore, lipid imbalance may be a critical event in FRDA progression [75].…”