While nearly all cells of the body can experience stress caused by extrinsic or intrinsic factors (changes in nutrient availability, infection, etc), some cell types such as photoreceptors, adipose tissues, and hepatocytes (liver cells) operate under elevated levels of basal cellular stress due to their function. The presence of disease-causing mutations further exacerbates cellular stress in these cell types, resulting to rapid decline in tissue health and functionality. Even in healthy individuals, the ability to cope with cellular stress generally declines with age, leading to progressive loss in vision and metabolic diseases respectively.
How can we improve stress tolerance?
What makes a photoreceptor more resistant to degeneration than its neighbors?
Does prior exposure to stress make a cell more or less proficient in dealing with new stressors?
To answer these questions, Drosophila (fruit flies) are an unmatched model as far as availability of genetic tools and ease of husbandry go, which makes it our favorite discovery platform. We also do a fair bit of cell culture and collaborate with other labs that work on vertebrate models to corroborate our findings.
Metazoans have evolved a variety of different stress responsive signaling pathways that help minimize cellular damage and restore homeostasis. A majority of these pathways engage transcription programs to alleviate stress. Of course, it is not sufficient for an mRNA to be transcribed but it must also be translated for it to exert its effect. Turns out, some pathways, such as the Integrated Stress Response (ISR), regulate both transcription and translation in response to stress. Specifically, they reduce the availability of certain factors require for initiation of mRNA translation, such that only mRNAs with certain features are effectively translated under these conditions. We recently found that there are non-canonical translation factors that aid the translation of these 'select' mRNAs, such as the one encoding the master stress response transcription factor ATF4 (PMC7495428).
We are currently trying to figure out the molecular mechanisms of non-canonical translation factors we identified in a genetic screen for regulators of ISR signaling. We are particularly invested in understanding how these factors impact cells like photoreceptors that have a high basal level of cellular stress due to their function (your photoreceptors are working quite hard to be able to read this!).
Drosophila have compound eyes consisting of ~800 individual units ('ommatidia') each. Each ommatidium has a cluster of photoreceptors that can be easily observed non-invasively using fluorescent markers such as the one shown above.
A fly model of autosomal dominant Retinitis Pigmentosa using the Rh1G69D allele shows early stage photoreceptor photoreceptor degeneration (yellow outline) amidst healthy photoreceptor clusters (white outline). Genetic depletion of ATF4 in similar aged flies substantially exacerbates photoreceptor degeneration (right).
The activation of the ISR signaling by PERK, which responds to perturbations in ER homeostasis, has different outcomes in different contexts: in some ophthalomogical disorders such as retinitis pigmentosa where vision degrades with age, the activation of PERK has a protective effect (PMC6583901, PMC7495428); in other neurodegenerative disorders inhibition of PERK leads to better outcomes in terms of cell viability (PMC3033190, PMC5010237). The fly eye is a great platform to study this because both protective and degenerative effects can be modeled in the same tissue. We're hoping to make a dent in our understanding of this dual nature of PERK activation using this model.
Similar to photoreceptors, ,metabolism-intensive tissues such as adipose or liver are also under chronic stress, and are reliant on ISR signaling for maintaining homeostasis. In addition to cell-autonomous effects on lipid accumulation and plaque formation, we've found that ISR signaling in these tissues have non-autonomous effects on other bodily functions such as oogenesis. We are dissecting how ISR signaling impacts inter-organ communication in this context.
Confocal microscopy image of a Drosophila ovary showing individual egg chambers that represent various stages of oogenesis. The nuclear envelope is marked in red (Lamin) and nuclei are counterstained in blue (DAPI).