Intrinsic Neuronal Injury Responses in Neurodegeneration: Transcriptional Regulation, Structural Plasticity, and Translational Human Model Systems

Neurodegenerative disorders, such as Alzheimer’s and Parkinson’s disease, are defined by progressive neuronal injury, synaptic dysfunction, and the breakdown of neural circuits. While extensive research has historically focused on pathogenic proteins and genetic risk factors, less attention has been given to understanding how neurons intrinsically respond to sustained injury and chronic stress at cellular and transcriptional levels. Understanding these intrinsic neuronal response programs is essential for determining why compensatory mechanisms—such as axonal remodeling, metabolic adjustments, and transcriptional reprogramming—initially delay degeneration but ultimately fail as the disease progresses. Recent advancements in super-resolution microscopy and spatially resolved transcriptomics now enable the visualization of these processes with unprecedented precision. By linking neuronal structure and function with gene regulation, we can begin to decode the complex relationship between cellular adaptation and the eventual collapse of neural integrity in the aging brain.The primary goal of this Research Topic is to investigate how neurons respond to intrinsic injury and pathological stress, specifically focusing on the transcriptional and epigenetic regulatory mechanisms that influence adaptation and survival. A critical challenge in the field is understanding the spatial and temporal orchestration of these responses and identifying the exact mechanisms that lead to their failure during disease progression. To address this, we aim to integrate molecular profiling, single-cell transcriptomics, and high-resolution imaging to examine injury responses at both cellular and subcellular levels. Furthermore, we seek to address the gap in translational fidelity by encouraging the use of innovative model systems—such as human iPSC-derived neurons and 3D organoids—that are systematically benchmarked against human neuropathological specimens. By combining advanced imaging with multi-omic profiling, the goal is to move beyond merely describing disease markers toward gaining mechanistic insights into neuronal resilience. Ultimately, this topic aims to identify new therapeutic strategies designed to reinforce protective programs and preserve circuit integrity.This Research Topic defines its scope around the intrinsic mechanisms of neuronal resilience and the failure of compensatory programs in neurodegeneration. We invite contributors to address specific themes, including:• Transcriptional and epigenetic regulation of neuronal adaptation.• Structural remodeling and synaptic plasticity in response to chronic stress.• The development and benchmarking of human-derived translational models (iPSCs, organoids, organ-on-chip) against patient-derived datasets.We are particularly interested in manuscripts that utilize spatial transcriptomics or high-resolution microscopy to link gene expression with cellular morphology. We welcome various manuscript types, including Original Research, Reviews, and Method papers that offer mechanistic insights or suggest clinically informed intervention strategies. Submissions should emphasize translational validity and the identification of conserved injury-response programs that can be therapeutically targeted to enhance regeneration and slow disease progression. Topic editors: Sadik Bay, Nese Ayşit, Aftab Alam, Okan Yildirim Source: https://www.frontiersin.org/research-topics/77949/intrinsic-neuronal-injury-responses-in-neurodegeneration-transcriptional-regulation-structural-plasticity-and-translational-human-model-systems