Uncovering injury-specific proteomic signatures and neurodegenerative risks in single and repetitive traumatic brain injury | Signal Transduction and Targeted Therapy – Nature

Report on Proteomic Signatures and Neurodegenerative Risks in Traumatic Brain Injury

Introduction

Traumatic brain injury (TBI) represents a significant global health challenge, contributing to increased risks of neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). This study focuses on the molecular and behavioral consequences of single and repetitive mild TBI (mTBI) in a mouse model, emphasizing the Sustainable Development Goals (SDGs) related to health and well-being (SDG 3) and innovation in scientific research (SDG 9).

Objectives

1. To investigate proteomic changes in the cortex and hippocampus following single and repetitive mTBI at acute (48 hours) and subacute (1 week) stages.
2. To assess motor and cognitive behavioral outcomes post-injury at 2, 7, and 30 days.
3. To identify molecular networks linked to neurodegenerative pathways as potential biomarkers or therapeutic targets.

Methodology

Experimental Design

• Male C57BL/6 mice subjected to single (smTBI) or repetitive (rmTBI, three hits) mild TBI using a modified closed head injury model.
• Proteomic profiling conducted via shotgun proteomics using LC-MS/MS at 48 hours and 1 week post-injury in cortex and hippocampus.
• Protein-protein interaction (PPI) and weighted gene co-expression network analysis (WGCNA) applied to identify protein networks.
• Behavioral tests including pole climbing, grip strength, Morris water maze (MWM), and elevated plus maze (EPM) conducted at acute, subacute, and chronic stages.

Data Analysis

• Proteomic data processed with MaxQuant and Proteome Discoverer software.
• Machine learning models (LDA, LightGBM, Ridge) applied for classification and biomarker identification.
• Gene Ontology (GO) enrichment analyses performed to identify biological processes affected.

Results

Proteomic Changes and Molecular Pathways

1. Identification of 3,637 proteins with 2,070 significantly deregulated post-TBI.
2. Distinct proteomic profiles observed between single and repetitive injuries, with repetitive TBI showing exacerbated neuronal damage and synaptic deficits.
3. Key deregulated proteins linked to neurodegenerative diseases include Apoa1, ApoE, Cox6a1, Snca, and others associated with mitochondrial function and synaptic integrity.
4. GO enrichment revealed upregulation of inflammatory and ribosomal biogenesis processes at 48 hours, and downregulation of mitochondrial ATP synthesis and cellular respiration pathways at 1 week.
5. WGCNA identified modules of co-expressed proteins associated with mitochondrial activity and metabolic processes (brown module) increased in repetitive TBI, and modules related to cytoskeletal organization and synaptic function (purple module) decreased in repetitive TBI.

Behavioral Outcomes

• Both single and repetitive mTBI impaired gross motor function at acute and subacute stages, with recovery by 30 days.
• Repetitive mTBI caused significant deficits in spatial learning and memory at subacute and chronic stages, as evidenced by Morris water maze performance.
• Anxiety-like behavior was not significantly affected by either injury type, indicating specific cognitive and motor impairments.

Discussion

Implications for Sustainable Development Goals

• SDG 3 (Good Health and Well-being): Understanding proteomic alterations and behavioral deficits in TBI supports the development of diagnostic biomarkers and therapeutic targets, aiming to reduce the burden of neurodegenerative diseases linked to brain injury.
• SDG 9 (Industry, Innovation, and Infrastructure): The integration of advanced proteomics, bioinformatics, and machine learning exemplifies innovative approaches to biomedical research, fostering scientific progress and personalized medicine.
• SDG 10 (Reduced Inequalities): Insights from this research can contribute to equitable healthcare by improving outcomes for populations at risk of TBI-related neurodegeneration.

Key Findings

1. Repetitive mTBI exacerbates mitochondrial dysfunction, neuroinflammation, and synaptic deficits, increasing neurodegenerative risk.
2. Single mTBI triggers neuroprotective and repair mechanisms, indicating potential for recovery with appropriate interventions.
3. Proteomic signatures identified provide candidate biomarkers for early diagnosis and targets for therapeutic development.
4. Behavioral impairments correlate with molecular changes, emphasizing the importance of mitochondrial and synaptic integrity in TBI response.

Limitations and Future Directions

• Effects of repeated anesthesia in sham controls were not evaluated; future studies should include anesthesia-only controls.
• Long-term proteomic changes beyond 30 days post-injury remain to be investigated to understand chronic neurodegeneration.
• Further validation of identified biomarkers and therapeutic targets is required through extended preclinical and clinical studies.

Conclusion

This comprehensive study elucidates the injury-specific proteomic and behavioral alterations following single and repetitive mild traumatic brain injury, highlighting molecular pathways linked to neurodegenerative diseases. The findings emphasize the critical role of mitochondrial function, inflammatory response, and synaptic regulation in TBI pathology and recovery. By aligning with the Sustainable Development Goals, particularly SDG 3 and SDG 9, this research contributes to advancing health outcomes and fostering innovation in neurotrauma research. The identified molecular networks and biomarkers offer promising avenues for developing interventions to mitigate long-term cognitive decline and improve quality of life for individuals affected by repetitive head trauma.

1. Sustainable Development Goals (SDGs) Addressed or Connected to the Issues Highlighted in the Article

1. SDG 3: Good Health and Well-being
   • The article focuses on traumatic brain injury (TBI), a major public health concern affecting neurological health, cognitive and motor functions, and risk of neurodegenerative diseases.
   • It addresses prevention, treatment, and rehabilitation aspects related to brain injuries and associated neurodegenerative risks.
2. SDG 9: Industry, Innovation and Infrastructure
   • The study employs advanced proteomic technologies, machine learning, and bioinformatics to uncover molecular mechanisms and biomarkers, contributing to innovation in medical research and diagnostics.
3. SDG 4: Quality Education
   • The article discusses cognitive impairments and learning deficits following TBI, highlighting the importance of cognitive health and recovery, which relate to educational outcomes and lifelong learning.

2. Specific Targets Under Those SDGs Identified Based on the Article’s Content

1. SDG 3: Good Health and Well-being
   • Target 3.4: By 2030, reduce by one third premature mortality from non-communicable diseases through prevention and treatment and promote mental health and well-being.
   • Target 3.8: Achieve universal health coverage, including access to quality essential health-care services and access to safe, effective, quality, and affordable essential medicines and vaccines for all.
   • Target 3.b: Support the research and development of vaccines and medicines for the communicable and non-communicable diseases that primarily affect developing countries.
2. SDG 9: Industry, Innovation and Infrastructure
   • Target 9.5: Enhance scientific research, upgrade the technological capabilities of industrial sectors, including encouraging innovation and substantially increasing the number of research and development workers.
3. SDG 4: Quality Education
   • Target 4.1: Ensure that all girls and boys complete free, equitable and quality primary and secondary education leading to relevant and effective learning outcomes.
   • Target 4.7: Ensure that all learners acquire the knowledge and skills needed to promote sustainable development, including health and well-being.

3. Indicators Mentioned or Implied in the Article to Measure Progress Towards the Identified Targets

1. Health and Well-being Indicators (SDG 3)
   • Incidence and prevalence rates of traumatic brain injury (TBI) and related neurodegenerative diseases such as Alzheimer’s disease (AD) and Parkinson’s disease (PD).
   • Behavioral assessments measuring motor function (pole climbing test, grip strength test) and cognitive function (Morris water maze test) post-injury at various time points (acute, subacute, chronic stages).
   • Biomarkers identified through proteomic analysis (e.g., Apoa1, ApoE, Cox6a1, Snca, Tau protein) for diagnosis, prognosis, and therapeutic targeting of TBI and neurodegeneration.
   • Levels of inflammation and mitochondrial dysfunction as molecular indicators of injury severity and recovery.
2. Innovation and Research Indicators (SDG 9)
   • Number and quality of scientific studies employing advanced proteomics, machine learning, and bioinformatics for TBI research.
   • Development and validation of molecular biomarkers and therapeutic targets for TBI and neurodegenerative diseases.
3. Education and Cognitive Function Indicators (SDG 4)
   • Performance metrics in learning and memory tests (e.g., latency and time spent in target quadrants in Morris water maze) as proxies for cognitive health and educational outcomes.
   • Assessment of anxiety-like behavior to rule out confounding factors affecting cognitive performance.

4. Table of SDGs, Targets, and Indicators Relevant to the Article

Source: nature.com