Biology subjects

Kussick, E.

Publications and source records attributed to Kussick, E..

3 recordsLinked to original sources

bioRxiv2026

A consensus spinal cord cell type atlas across mouse, macaque, and human

The spinal cord contains evolutionarily conserved cell types critical for motor function, sensory processing, and autonomic regulation, many of which are implicated in diverse neurological diseases and injuries. Yet the field lacks a comprehensive molecular characterization of cellular diversity in human, macaque, and mouse spinal cord. Here, we present a unified, cross-species cell type atlas based on the integration of single-nucleus gene expression, chromatin accessibility, and spatial transcriptomic data from segments within cervical, thoracic, lumbar, and sacral regions, including motor neurons (MNs) sampled across the entire rostro-caudal axis of the macaque spinal cord. Leveraging the spatial distributions of our molecularly defined cell types, we generated a cell type-guided anatomical map of spinal cord laminae and nuclei. We identified both conserved and species-specific cellular features, including gene expression patterns across distinct MN subtypes in the primate spinal cord. Cross-species cis-regulatory analysis and deep learning sequence models dissected the enhancer logic underlying viral targeting, uncovering conserved transcription factor grammar encoding cellular identity. Together, these results establish a unifying molecular and anatomical taxonomy of spinal cord cell types across species.

neuroscience↗

bioRxiv2026

Enhancer-based AAV approach for selective AADC delivery reduces motor symptoms and dyskinesia in Parkinson's mouse models

Degeneration of midbrain dopamine (DA) neurons and the resulting loss of striatal dopamine signaling are hallmarks of Parkinsons disease (PD). Although the dopamine precursor levodopa (L-DOPA) provides symptomatic relief, prolonged treatment often leads to abnormal involuntary movements (dyskinesia). Previous adeno-associated virus (AAV) approaches delivering aromatic L-amino acid decarboxylase (AADC) to the striatum under a ubiquitous promoter enhanced local dopamine synthesis and improved PD motor deficits, but this broad targeting strategy limited insight into the cellular populations underlying the behavioral improvements. Here, we engineered enhancer-driven AAVs to direct AADC expression to defined striatal and midbrain cell populations and paired these regulatory elements with a blood-brain barrier-penetrant capsid to enable both systemic and direct delivery. Targeted expression restored motor performance at reduced L-DOPA doses and decreased dyskinesia-like behaviors, producing improvements comparable to or greater than those achieved with ubiquitous expression. Distinct neuronal and non-neuronal populations each supported motor rescue but improved different behavioral domains to different extents, indicating complementary cell type-specific roles within PD-relevant circuits. Together, these findings establish enhancer-driven, cell type-specific AADC delivery as a better-tolerated strategy that enables rescue of motor deficits at lower L-DOPA doses in PD models.

neuroscience↗

bioRxiv2024

Enhancer AAVs for targeting spinal motor neurons and descending motor pathways in rodents and macaque

Experimental access to cell types within the mammalian spinal cord is severely limited by the availability of genetic tools. To enable access to lower motor neurons (LMNs) and LMN subtypes, we generated single cell multiome datasets from mouse and macaque spinal cords and discovered putative enhancers for each neuronal population. We cloned these enhancers into adeno-associated viral vectors (AAVs) driving a reporter fluorophore and functionally screened them in mouse. We extensively characterized the most promising candidate enhancers in rat and macaque and developed an optimized pan LMN enhancer virus. Additionally, we generated derivative viruses expressing iCre297T recombinase or ChR2-EYFP for labeling and functional studies, and we created a single vector with combined enhancer elements to achieve simultaneous labeling of layer 5 extratelencephalic projecting (ET) neurons and LMNs. This unprecedented LMN toolkit will enable future investigations of cell type function across species and potential therapeutic interventions for human neurodegenerative diseases.

neuroscience↗