A major challenge in neuroscience is capturing and manipulating neuronal signaling and modulation both with high spatiotemporal resolution and across a large brain volume. Another significant hurdle lies in the lack of reagents to selectively target misfolded a-synuclein (a-syn) protein aggregates, a hallmark feature observed in various neurodegenerative diseases, including Parkinson’s disease and Lewy body dementia. 

To address both of these challenges, the Wang research group takes a chemical biology approach to design novel classes of protein-based sensors, tools and reagents as described below.

Designing integrators for mapping neuromodulators with high spatial and temporal resolution across the brain

Neuromodulators, such as neural peptides and monoamines, play critical roles in modulating the activity of a range of neuronal circuits. Studying when and where neuromodulators are released and transmitted is crucial for a better understanding of how the neuromodulators exert their effects on targeted neuronal populations. 

Our group focuses on designing integration sensors (integrators) that can detect neuromodulation signals and leave a mark on the neurons to enable detection across large brain volume at high spatial resolution. We have designed various genetically-encoded tools for mapping neuromodulators with high spatiotemporal resolution.

Designing new classes of optogenetic and chemogenetic tools for prolonged neuronal silencing with a fast temporal control

Optogenetic and chemogenetic tools that enable activation or inhibition of selective neuronal populations with temporal control have significantly advanced neuroscience. We focus on designing new classes of optogenetic and chemogenetic tools to regulate endogenous neuromodulatory systems to study their causal effect. 

Via directed evolution, we designed the first generally applicable chemical-dependent protein switches called CAPs (Chemically Activated Protein domains) to control the accessibility of the N- or C-terminal region of a peptide embedded within the protein domain. We demonstrated the generality of the CAPs system in controlling the activity of peptides in cell cultures, mouse brain, and liver. We have also designed a new photo-switchable domain for caging the C-terminal region of a peptide to expand the design of optogenetic control of receptor activity. In future work, we will apply these protein switches to design genetically encoded and temporally gated GPCR peptide agonists, which enable unprecedented manipulations of endogenous neuromodulation.

Protein-based reagents for targeting alpha-syn pathology in Parkinson’s diseases

Nanobodies, derived from the single-chain antibodies from Camelidae, provide excellent alternatives to conventional antibodies for recognizing various protein targets. They are much smaller, more stable and more soluble than conventional antibodies. 

Due to their advantages, nanobodies have been widely applied as research tools and hold tremendous promise as therapeutic reagents. We have designed a α-syn fibril-selective nanobody which also inhibits α-syn pathology development in mouse models of Parkinson's disease. Further work is underway to evaluate its long term effect and therapeutic potential.