Dysfunction in cellular energy homeostasis is a defining feature of Alzheimer disease (AD) and related dementias. Importantly, the expression of most mitochondrial genes is downregulated in the brain of patients with AD but the mechanisms responsible for these AD-associated transcriptional changes are largely unknown. Moreover, many studies indicate that mitochondria from AD patients differ structurally and functionally from those of control individuals. On the basis of these findings, improving mitochondrial gene expression and function has been proposed as a therapy to block or delay the progression of AD. However, no such therapy is available. In R01-funded research, we are investigating the role of the myokine (a muscle-secreted factor) Myoglianin, the Drosophila homolog of human GDF11. As in humans, mitochondrial dysfunction is a prevalent feature of tissue aging in Drosophila. We find that Myoglianin promotes mitochondrial gene expression and maintains mitochondrial function during skeletal muscle aging via the transcription factor vismay/TGIF (TGFb-induced factor). Interestingly, its human homolog TGIF1 has been recently identified as a key neuroprotective master regulator of transcriptional changes in AD pathogenesis, based on the analysis of transcriptome and proteome data from brains of neuropathologically-confirmed AD patients compared to age-matched non-demented controls. On this basis, we propose to expand our R01-funded studies to explore the relevance of GDF11/TGIF signaling for brain aging and AD-like conditions in Drosophila. Specifically, we propose to test whether GDF11 receptor/TGIF signaling contrasts the decline in mitochondrial gene expression and function that occurs in the brain during aging and in an AD-like condition (pathogenic tau overexpression). Considering that TGIF1 has been recently implicated in AD and that GDF11 has been already involved in brain rejuvenation via undefined mechanisms, our studies promise to provide mechanistic understanding on how GDF11/TGIF signaling preserves brain function during aging. In summary, these studies propose to test in Drosophila the role of GDF11/TGIF signaling in modulating mitochondrial gene expression and function during brain aging and in AD-like conditions. Knowledge gained from these studies will provide fundamental understanding of the interconnection of mitochondrial dysfunction with AD, and explore the efficacy of GDF11/TGIF-based interventions for this pathogenic component of AD.
Decline in mitochondrial gene expression is a defining feature of Alzheimer disease (AD) and related dementias. Here, we propose to expand our R01-funded research to investigate the role of GDF11/TGIF signaling in maintaining mitochondrial gene expression and function in the brain during aging and in AD-like conditions in Drosophila. Our studies promise to provide mechanistic understanding on how GDF11/TGIF signaling protects from AD pathogenesis.
