Biology subjects

Hutson, T.

Publications and source records attributed to Hutson, T..

3 recordsLinked to original sources

bioRxiv2024

THE NEURONAL ARCHITECTURE OF AUTONOMIC DYSREFLEXIA

Autonomic dysreflexia is a life-threatening medical condition characterized by episodes of uncontrolled hypertension that occur in response to sensory stimuli after spinal cord injury (SCI)1-7. The fragmented understanding of the mechanisms underlying autonomic dysreflexia hampers the development of therapeutic strategies to manage this condition, leaving people with SCI at daily risk of heart attack and stroke8-18. Here, we expose the complete de novo neuronal architecture that develops after SCI and causes autonomic dysreflexia. In parallel, we uncover a competing, yet overlapping neuronal architecture activated by epidural electrical stimulation of the spinal cord that safely regulates blood pressure after SCI. The discovery that these adversarial neuronal architectures converge onto a single neuronal subpopulation provided a blueprint for the design of a mechanism-based intervention that reversed autonomic dysreflexia in mice, rats, and humans with SCI. These results establish a path for the effective treatment of autonomic dysreflexia in people with SCI.

neuroscience↗

bioRxiv2023

The Tabulae Paralytica: Multimodal single-cell and spatial atlases of spinal cord injury

Here, we introduce the Tabulae Paralytica--a compilation of four atlases of spinal cord injury (SCI) comprising a single-nucleus transcriptome atlas of half a million cells; a multiome atlas pairing transcriptomic and epigenomic measurements within the same nuclei; and two spatial transcriptomic atlases of the injured spinal cord spanning four spatial and temporal dimensions. We integrated these atlases into a common framework to dissect the molecular logic that governs the responses to injury within the spinal cord. The Tabulae Paralytica exposed new biological principles that dictate the consequences of SCI, including conserved and divergent neuronal responses to injury; the priming of specific neuronal subpopulations to become circuit-reorganizing neurons after injury; an inherent trade-off between neuronal stress responses and the activation of circuit reorganization programs; the necessity of reestablishing a tripartite neuroprotective barrier between immune-privileged and extra-neural environments after SCI; and a catastrophic failure to form this barrier in old mice. We leveraged the Tabulae Paralytica to develop a rejuvenative gene therapy that reestablished this tripartite barrier, and restored the natural recovery of walking after paralysis in old mice. The Tabulae Paralytica provides an unprecedented window into the pathobiology of SCI, while establishing a framework for integrating multimodal, genome-scale measurements in four dimensions to study biology and medicine.

genomics↗

bioRxiv2019

Combinatorial proteomics and transcriptomics identify AMPK in the control of the axonal regeneration programme of DRG sensory neurons after spinal injury

Regeneration after injury occurs in axons that lie in the peripheral nervous system but it fails in the central nervous system limiting functional recovery. Despite recent progress, the signalling response to injury of peripheral versus central projecting axons that might underpin this differential regenerative ability is currently largely uncharacterized. To fill this knowledge gap, here we combined axoplasmic proteomics from peripheral sciatic or central projecting dorsal root axons from sciatic DRG neurons. Proteomics was combined with cell body RNAseq to compare axonal and soma responses between a spinal regeneration-incompetent versus sciatic regeneration-competent nerve injury. This allowed the identification of injury-dependent signalling pathways uniquely represented in peripheral versus central projecting sciatic DRG axons. RNAseq and proteomics analysis suggested AMPK as a putative regulator of axonal regenerative signalling pathways. AMPK immunoprecipitation followed by mass spectrometry from DRG suggested that the 26S proteasome and its regulatory subunit PSMC5 preferentially interact with AMPK for proteasomal degradation following sciatic axotomy. Mechanistically, we found that the proteasome and CaMKII-dependent proteasomal subunit PSMC5 regulates AMPK1 protein expression. Finally, conditional deletion of AMPK1 promoted multiple regenerative signalling pathways and robust axonal growth across the injured spinal cord, suggesting inhibition of AMPK as a novel regenerative target following spinal injury.\n\nHIGHLIGHTSO_LIAxoplasmic proteomics from sciatic or centrally projecting branches of sciatic DRG identifies unique protein enrichment and signalling pathways, including prior and subsequent to a spinal regeneration-incompetent versus sciatic regeneration-competent axonal injury\nC_LIO_LICombined axoplasmic DRG proteomics and cell body RNAseq analysis suggest AMPK as a central regulator controlling axonal regeneration\nC_LIO_LIThe 26S proteasome and the 19S regulatory subunit PSMC5 interact with AMPK following sciatic axotomy. PSMC5 regulates AMPK1 protein levels\nC_LIO_LIAMPK1 conditional deletion enhances robust axonal growth following SCI\nC_LI

neuroscience↗