Signaling in Neural Development and Neurodegeneration

Applying in vivo proteomics and genetic approaches to study pathways in nervous system development and neurodegenerative disease

Technology Overview

The Grill lab’s overarching interest is understanding how signaling influences nervous system development, function, and maintenance. The group pioneers both discovery-based and translational efforts in this area using the microscopic nematode Caenorhabditis elegans. C. elegans is amenable to large-scale genetic and behavioral screens. The Grill group developed C. elegans in vivo proteomics to determine how the nervous system is built and modulated. Their overall biomedical goal is finding targets for prevention and treatment of neurodegenerative disease and neurodevelopmental disorders.

Dr. Brock Grill

One major research area is the ubiquitin ligase RPM-1 (human ortholog PAM/MYCBP2), which the Grill lab has shown regulates axon termination and synapse maintenance. RPM-1 functions as a signaling hub and ubiqiuitin ligase that influences a signaling network that affects nervous system development. This RPM-1 signaling network also features prominent connections to neurodegenerative conditions such as axon degeneration following injury and Alzheimer’s disease. Emerging links between the RPM-1 network and neurodevelopmental disorders heighten the Grill lab’s interest in this research direction.

A second major focus is investigating the C. elegans homolog of HUWE1. This human ubiquitin ligase causes neurodevelopmental disorders including a rare X-linked disease, Juberg-Marsidi-Brooks syndrome, and non-syndromic X-linked intellectual disability. The Grill lab found that C. elegans HUWE1 is required for inhibitory GABAergic presynaptic transmission and excitatory/inhibitory balance in a simple model circuit. In vivo proteomics and functional genetics has begun to reveal molecular mechanisms by which HUWE1 affects GABA neuron function.

Dr. Grill has experience working with small biotech startups. He is interested in collaborations that use his C. elegans systems and expertise in in vivo proteomics and genetics for therapeutic discovery and development.

Stage of Development

• Preclinical in vivo
• Preclinical in vitro
• Licensing opportunities

Partnering Opportunities

• Collaborative research and development
• Sponsored research agreement
• Consultation agreement
• C. elegans model access and development

Publications

1. Giles AC, Grill B. Roles of the HUWE1 ubiquitin ligase in nervous system development, function and disease. Neural Dev. 2020 Apr 26;1(15)6.
2. Borgen MA, Giles AC, Wang D, Grill B. Synapse maintenance is impacted by ATAT-2 tubulin acetyltransferase activity and the RPM-1 signaling hub. Elife. 2019 Jan 18;8:e44040.
3. Crawley O, Opperman KJ, Desbois M…Grill B. Autophagy is inhibited by ubiquitin ligase activity in the nervous system. Nat Commun 2019 Nov 1;1(10):5017.
4. Giles AC, Desbois M, Opperman KJ, Tavora R, Maroni MJ, Grill B. A complex containing the O-GlcNAc transferase OGT-1 and the ubiquitin ligase EEL-1 regulates GABA neuron function. J Biol Chem. 2019 Apr 26;294(17):6843-6856.
5. Borgen MA, Wang D, Grill B. RPM-1 regulates axon termination by affecting growth cone collapse and microtubule stability. Development. 2017 Dec 15;144(24):4658-4672.