Transcriptional control of proteostasis and aging

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Project Summary/Abstract: The mechanisms that maintain proteome folding and function (proteostasis), become ineffective during normal aging, contributing to the onset and progression of neurodegenerative protein misfolding diseases- including Alzheimer’s Disease. Proteostasis is sustained through integrated processes involving coordinated regulation of protein synthesis, folding, and degradation in response to diverse signals. We have identified the homeodomain- interacting protein kinase (HPK-1) as a key regulator of aging and proteostasis. Constitutive expression of hpk- 1, is sufficient to delay aging, preserve proteostasis, and promote stress resistance, while loss of hpk-1 impairs stress resistance, accelerating aging and the deterioration of the proteome. HPK-1 acts via the heat shock transcription factor (HSF-1), and the target of rapamycin complex 1 (TORC1). HPK-1 antagonizes sumoylation of HSF-1, presumably to repress gene expression. HPK-1 extends longevity by an additional independent mechanism: induction of autophagy via dietary restriction or TORC1 inactivation. HPK-1 expression is itself regulated by distinct mechanisms after nutritional or thermal stress, implying that HPK-1 may function as part of an integrated stress response to maintain proteostasis. Notably, we also have found that hpk-1 is required for maintaining proteostasis in C. elegans neurons, and a recent study found induced expression of a mammalian homolog in regions of the brain affected by neurodegeneration in Alzheimer’s Disease and Amyotrophic Lateral Sclerosis patients, suggesting an induced stress response. Our hypothesis is that HPK-1 prevents the age- associated decline of proteostasis by suppressing protein misfolding and stimulating protein turnover through the regulated gene expression of chaperones and autophagy, respectively. We will gain mechanistic insight into how HPK-1 regulates HSF-1 and affects aging and proteostasis through the use of proteomics and CRISPR/Cas9 targeted mutagenesis. We will apply combinations of stressors and activated HPK-1 to understand how HPK-1 functions as a part of an integrated system to maintain proteome function. We utilize genetic, genomic, and systems biology approaches to explore how dynamic regulation of the proteostatic network safeguards proper function of the proteome. In addition, we will employ tissue-specific gene manipulation to understand how this network acts across tissues. To determine the physiological consequences of hpk-1 on neuronal proteostasis and degeneration we will utilize a polyglutamine reporter and isoforms of tau to induce proteotoxicity within C. elegans neurons. Additionally, we will determine the role of Hipk1-3 loss (mammalian homologs of hpk-1) in the context of pharmacological interventions targeted to reduce proteotoxic effects of tau in mammalian neurons. With this work we will gain understanding of the role of HPK-1 during aging in the regulation of the proteostatic network, and insight into the manifestation of neurodegenerative diseases.