# High Throughput screen to identify "first of their kind" activators of ADCY10

> **NIH NIH R01** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $588,072

## Abstract

Aberrant accumulation of protein aggregates is a common feature of age-related
neurodegenerative diseases, including Alzheimer's disease. Cells clear aggregated material via
autophagy. Lysosomes, the acidic organelles where proteins and unused cellular components
are degraded and recycled, are the terminal compartment of autophagy. Long-lived, post-mitotic
cells such as neurons are dependent upon continuous lysosomal turnover of cellular materials
delivered by autophagy. With aging, lysosomes become less acidic, and their proteolytic activity
decreases. In a cellular model of Alzheimer's disease, re-acidification of lysosomal pH increases
autophagic flux and rescues cell function. We discovered a signaling cascade which regulates
lysosomal acidification. Soluble adenylyl cyclase (sAC) is a source of the ubiquitous second
messenger cAMP which is molecularly, structurally, biochemically, and functionally distinct from
the family of plasma membrane-bound, hormone-regulated transmembrane forms of adenylyl
cyclase. We showed sAC-generated cAMP promotes lysosomal acidification, and in the absence
of sAC activity, autophagic flux is slowed. There are no pharmacological activators of sAC. We
previously used high throughput screening to identify the most widely used pharmacological
inhibitors specific sAC. We now propose to use high throughput screening and our battery of in
vitro and cellular sAC assays to identify and characterize “first-of-their kind” small molecule
activators selective for sAC usable in cellular systems. We hypothesize that sAC activators will
facilitate lysosomal acidification and increase degradation of accumulated protein aggregates in
cellular models of neurodegenerative disorders. These studies have the potential to supply proof-
of-principle for a therapeutic strategy to treat neurodegenerative disorders.

## Key facts

- **NIH application ID:** 9856410
- **Project number:** 5R01AG061290-02
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** JOCHEN BUCK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $588,072
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9856410

## Citation

> US National Institutes of Health, RePORTER application 9856410, High Throughput screen to identify "first of their kind" activators of ADCY10 (5R01AG061290-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9856410. Licensed CC0.

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