Cathepsin B Relocalization in Late Membrane Disrupted Neurons Following Diffuse Brain Injury in Rats
Open accessAbstract
Traumatic brain injury (TBI) has consequences that last for years following injury. While TBI can precipitate a variety of diffuse pathologies, the mechanisms involved in injury-induced neuronal membrane disruption remain elusive. The lysosomal cysteine protease, Cathepsin B (Cath B), and specifically its redistribution into the cytosol has been implicated in cell death. Little is known about Cath B or neuronal membrane disruption chronically following diffuse TBI. Therefore, the current study evaluated Cath B and diffuse neuronal membrane disruption over a more chronic post-injury window (6 h–4 w). We evaluated Cath B in adult male Sprague-Dawley rats following central fluid percussion injury (CFPI). Expression of Cath B, as well as Cath B-associated pro (Bak and AIF) and anti-apoptotic (Bcl-xl) proteins, were assessed using western blot analysis. Cath B activity was also assessed. Localization of Cath B was evaluated in the membrane disrupted and non-disrupted population following CFPI using immunohistochemistry paired with quantitative image analysis and ultrastructural verification. There was no difference in expression or activity of Cath B or any of the associated proteins between sham and CFPI at any time post-injury. Immunohistological studies, however, showed a sub-cellular re-localization of Cath B at 2 w and 4 w post-injury in the membrane disrupted neuronal population as compared to the time-point matched non-disrupted neurons. Both membrane disruption and Cath B relocalization appear linked to neuronal atrophy. These observations are indicative of a late secondary pathology that represents an opportunity for therapeutic treatment of these neurons following diffuse TBI. Summary Statement Lysosomal cathepsin B relocalizes to the cytosol in neurons with disrupted plasmalemmal membranes weeks following diffuse brain injury. Both the membrane disrupted and cathepsin B relocalized neuronal subpopulations displayed smaller soma and nucleus size compared to non-pathological neurons, indicating atrophy.
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Lysosomal cathepsins, such as cathepsin B, can induce NLRP3 inflammasome activation upon leaking into the cytosol following lysosomal membrane permeabilization (LMP).
“lysosomal cathepsins, such as cathepsin B, can induce NLRP3 inflammasome activation upon leaking into the cytosol following lysosomal membrane permeabilization (LMP)42,43”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [42]
The Discussion (page unavailable) says cathepsin B outside lysosomes could indicate lysosomal membrane permeabilization and proposes that LMP could release it into the cytosol. Neither that passage nor the Introduction identifies NLRP3 inflammasome activation as a consequence; searches for NLRP3 and inflammasome did not find support for that part of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCathepsin B leaking from destabilized lysosomes may mediate NLRP3 inflammasome activation upon SHIP1 inhibition.
“Based on the previous literature42,43,46, we reasoned that cathepsin B leaking from the destabilized lysosomes may mediate the NLRP3 inflammasome activation upon SHIP1 inhibition11.”
From INPP5D/SHIP1 regulates endo-lysosomal function and cargo-selective phagocytosis in human microglia (2025) · cites this paper as [42]
The Discussion (page unavailable) reports cathepsin B outside lysosomes after diffuse brain injury and suggests lysosomal membrane permeabilization could release it into the cytosol. Our copy does not link that release to NLRP3 inflammasome activation or SHIP1 inhibition, the condition next to this citation in the citing sentence. (LLM, conf=0.84)
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- Authors
- Hernandez, M. L., Marone, M., Gorse, K. M., & Lafrenaye, A. D.
- Affiliations
- Virginia Commonwealth University (US)
- Corresponding author
- Lafrenaye, Audrey D.
- Venue
- ASN Neuro
- Publisher
- Informa UK Limited
- Published
- 2022-01
- Volume
- 14
- Issue
- 1
- Pages
- 17590914221099112-17590914221099112
- ISSN
- 1759-0914 (ISSN-L)
- PMC
- PMC9069603
- OpenAlex
- W4225413452
- Cited by
- 10
- References
- 44
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 1 · 2022: 1
- FWCI
- 1.18
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- ASN NEURO (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- National Institute of Neurological Disorders and Stroke (1R01NS096143)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Automotive and Human Injury Biomechanics
- Keywords
- cathepsin B, diffuse traumatic brain injury, lysosomal cysteine proteases, protein relocalization, neuronal atrophy, Bak, AIF, Bcl-xL, apoptosis
- MeSH terms
- Brain Injuries, Diffuse, Brain Injuries, Traumatic, Animals, Atrophy, Cathepsin B, Male, Neurons, Rats, Sprague-Dawley, Rats
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