Systemic Neurodegeneration and Brain Aging: Multi-Omics Disintegration, Proteostatic Collapse, and Network Failure...

Area of Science:

• Neuroscience
• Cellular Biology
• Systems Biology
• Genetics

Background:

• Neurodegenerative diseases (ND) are increasingly viewed as complex breakdowns of biological organization, extending beyond simple protein aggregation.
• Existing models often overlook the intricate interplay of intracellular signaling, transcriptional regulation, proteostasis, and organelle communication in ND pathogenesis.
• A paradigm shift is needed to understand ND as a progressive failure of cellular interpretive logic and network-level computation.

Purpose of the Study:

• To synthesize emerging frameworks that reframe neurodegenerative diseases as progressive breakdowns of cellular interpretive logic.
• To map the spatial and temporal disintegration of critical signaling pathways and their impact on neuronal function.
• To explore novel therapeutic avenues focused on restoring neuronal agency and resilience.

Main Methods:

• Review and synthesis of current literature on signaling pathways (PI3K-AKT-mTOR, MAPK, Wnt/β-catenin, ISR) in neurodegeneration.
• Analysis of the roles of RNA-binding proteins, epitranscriptomic modifiers (m6A), and non-canonical post-translational modifications.
• Examination of organelle dysfunction, including ribosome-associated quality control, autophagy-lysosome machinery, and mitochondrial dynamics.
• Integration of single-cell and spatial transcriptomics data to understand network-level disruptions (DMN, SN, FPCN).

Main Results:

• Neurodegeneration is characterized by the disintegration of signaling pathways, disrupted proteostasis, and impaired organelle communication.
• RNA-binding proteins, epitranscriptomic modifiers, and aberrant post-translational modifications critically contribute to cellular dysfunction.
• Synaptic disassembly and network-level collapse (e.g., in DMN, SN, FPCN) are early events driven by proteostatic and metabolic stress.
• Failure in cellular reasoning, including signal interpretation and triage prioritization, underlies neurodegenerative processes.

Conclusions:

• Neurodegenerative diseases represent a systems-level failure of cellular reasoning and network coordination, not merely accumulation of toxic proteins.
• Therapeutic strategies should shift from damage containment towards restoring high-dimensional neuronal agency and resilience.
• Novel interventions may include proteome-targeting agents, engineered autophagy, gene enhancers, mitochondrial stabilizers, and glial-exosome neuroengineering.