Neuroanatomical zones of human traumatic brain injury reveal significant differences in protein profile and protein oxidation: Implications for secondary injury events

Niya Gowthami; Nithya Pursotham; Gourav Dey; Vivek Ghose; Gajanan Sathe; Nupur Pruthi; Dhaval Shukla; Narayanappa Gayathri; Rashmi Santhoshkumar; Balasundaram Padmanabhan; Vivek Chandramohan; Anita Mahadevan; M M Srinivas Bharath

doi:10.1111/jnc.15953

Neuroanatomical zones of human traumatic brain injury reveal significant differences in protein profile and protein oxidation: Implications for secondary injury events

J Neurochem. 2023 Oct;167(2):218-247. doi: 10.1111/jnc.15953. Epub 2023 Sep 11.

Authors

Niya Gowthami¹, Nithya Pursotham¹, Gourav Dey^{2

3}, Vivek Ghose^{2

3}, Gajanan Sathe^{2

3}, Nupur Pruthi⁴, Dhaval Shukla⁴, Narayanappa Gayathri⁵, Rashmi Santhoshkumar⁵, Balasundaram Padmanabhan⁶, Vivek Chandramohan⁷, Anita Mahadevan⁵, M M Srinivas Bharath¹

Affiliations

¹ Department of Clinical Psychopharmacology and Neurotoxicology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India.
² Proteomics and Bioinformatics Laboratory, Neurobiology Research Center, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India.
³ Institute of Bioinformatics, Bengaluru, India.
⁴ Department of Neurosurgery, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India.
⁵ Department of Neuropathology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India.
⁶ Department of Biophysics, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru, Karnataka, India.
⁷ Department of Biotechnology, Siddaganga Institute of Technology (SIT), Tumakuru, India.

PMID: 37694499
DOI: 10.1111/jnc.15953

Abstract

Traumatic brain injury (TBI) causes significant neurological deficits and long-term degenerative changes. Primary injury in TBI entails distinct neuroanatomical zones, i.e., contusion (Ct) and pericontusion (PC). Their dynamic expansion could contribute to unpredictable neurological deterioration in patients. Molecular characterization of these zones compared with away from contusion (AC) zone is invaluable for TBI management. Using proteomics-based approach, we were able to distinguish Ct, PC and AC zones in human TBI brains. Ct was associated with structural changes (blood-brain barrier (BBB) disruption, neuroinflammation, axonal injury, demyelination and ferroptosis), while PC was associated with initial events of secondary injury (glutamate excitotoxicity, glial activation, accumulation of cytoskeleton proteins, oxidative stress, endocytosis) and AC displayed mitochondrial dysfunction that could contribute to secondary injury events and trigger long-term degenerative changes. Phosphoproteome analysis in these zones revealed that certain differentially phosphorylated proteins synergistically contribute to the injury events along with the differentially expressed proteins. Non-synaptic mitochondria (ns-mito) was associated with relatively more differentially expressed proteins (DEPs) compared to synaptosomes (Syn), while the latter displayed increased protein oxidation including tryptophan (Trp) oxidation. Proteomic analysis of immunocaptured complex I (CI) from Syn revealed increased Trp oxidation in Ct > PC > AC (vs. control). Oxidized W272 in the ND1 subunit of CI, revealed local conformational changes in ND1 and the neighboring subunits, as indicated by molecular dynamics simulation (MDS). Taken together, neuroanatomical zones in TBI show distinct protein profile and protein oxidation representing different primary and secondary injury events with potential implications for TBI pathology and neurological status of the patients.

Keywords: contusion; mitochondria; pericontusion; protein oxidation; proteomics; synaptosomes.

Grants and funding

SERB-CRG/2018/001550/Science and Engineering Research Board