Traumatic axonopathies after diffuse TBI: the role of the SARM1 (Wallerian) pathway and DLK (MAPK) cascade
- NMNAT2-SARM1 signaling in traumatic axonopathy in the corticospinal and visual pathway: genetic (cre-lox, CRISPR) and pharmacological interventions for prevention and treatment of pathology and symptoms
(Top: compare injured axon with asterisk with the to the right of it)
and the formation of digestive or entrapment spheroids (Middle and Bottom, respectively)
Characterization of the effects of small molecules acting on NAD biosynthetic pathways on the outcome of Wallerian degeneration: NAMPT inhibitors, DLK inhibitors, NaR alone and in combination
Characterization and biomarking of early stages of axonopathies
The role of axonal injury in accelerating tauopathy in animals harboring pathogenic tau mutants or seeded with Alzheimer tau prions
Vagus nerve stimulation-based neuromodulation for neuroinflammation in neurotrauma and related conditions
The role of SARM1 in traumatic injury of the auditory system
Neuropathology of contusional and diffuse axonal injury in the human brain
Effects of such focal injuries are localized to thalamus, but secondary effects of diffuse white matter injury are throughout gray matter.
Traumatic axonopathies after diffuse TBI: the role of the SARM1 (Wallerian) pathway and DLK (MAPK) cascade
– NMNAT2-SARM1 signaling in traumatic axonopathy in the corticospinal and visual pathway: genetic (cre-lox, CRISPR) and pharmacological interventions for prevention and treatment of pathology and symptoms
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left: Acceleration injury in the optic tract generates end-bulbs, spindle-like axonal swellings and more classical Wallerian-type fragmentation. It is unclear if the above are part of the same continuum or distinct biological entities.
middle: Induction of the dual lineage kinase DLK (top) and downstream phosphorylation of c-JUN (bottom) in injured optic nerve and retina
right: Wallerian degeneration in the optic nerve after acceleration TBI (top). Knocking out DLK and LZK protects retinal ganglion cell bodies and the proximal segments of injured axons (bottom).
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left: Axonal pathology is featured by digestion of microtubules (Top: compare injured axon with asterisk with the to the right of it) and the formation of digestive or entrapment spheroids (Middle and Bottom, respectively)
middle: CRISPR/Cas9 based knockout of Sarm1 in combination with Dlk/Lzk is highly protective. A representative cleared ON at the chiasm shows marked suppression of axonopathy with combined Sarm1/Dlk/Lzk KO (right) compared to control (left).
right: CRISPR-based knockdown of SARM1 and DLK/LZK after injection of YFP-marked gRNA adenoviruses in thoracic cord. Gene-edited neurons/axons are labeled throughout the corticospinal tract, from spinal cord level (top) to medulla (middle) to motor cortex (bottom).
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left: Transcriptomic analysis on the visual system after TBI. TOP: On the left, single-cell RNA sequencing of retina shows the capture of all major retinal cell types. On the right, a heatmap of select genes in individual retinal ganglion cells shows that TBI causes upregulation of injury-response and downregulation of neuronal/synaptic identity genes. BOTTOM: On the left, Visium HD-based spatial transcriptomics in superior colliculus identifies clusters of transcripts by region and cell type. On the right, a heatmap of the top 10 differentially expressed genes in the optic region of superior colliculus (SGS). On the very right, spatial maps show upregulation of GFAP in the superficial superior colliculus across all TBI samples, highlighting glial activation.
right: Partial recovery of vision after diffuse TBI shown with pattern VEPs. Contrast sensitivity threshold comparisons in injured (red) and sham (black) mice from 7- to 56-day post injury in male (top) and female (bottom) mice show significant visual impairment (separation of lines indicates lower thresholds) followed by a sexually dimorphic recovery.