Gene Regulation in Neurodegeneration: A Comprehensive Review

Abstract

Gene regulation plays a central role in the complex etiology and progression of neurodegenerative diseases, orchestrating the delicate balance between neuronal survival and death. Neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia exhibit extensive transcriptional dysregulation involving key transcription factors like REST, CREB, and NF-κB. REST is protective during normal aging but becomes dysregulated in Alzheimer's disease, increasing neuronal susceptibility. CREB impairment compromises synaptic plasticity and cognitive function, whereas NF-κB hyperactivation fosters neuroinflammation, contributing to disease progression.

Epigenetic mechanisms including DNA methylation, histone modification, and chromatin remodeling add a critical regulatory layer influencing gene expression in neurodegeneration. Aberrations in methylation profiles, dysfunctional histone acetylation, and perturbations in chromatin remodeling complexes alter transcriptional landscapes, exacerbating neuronal loss. Therapeutic modulation of histone deacetylases via inhibitors has demonstrated promise in restoring gene expression patterns and neuroprotection in models of Alzheimer's and Huntington's diseases.

Non-coding RNAs such as microRNAs, long non-coding RNAs, and circular RNAs regulate gene expression post-transcriptionally with significant influence on neurodegenerative pathways. Dysregulated miRNAs affect critical proteins like amyloid precursor protein and alpha-synuclein, while lncRNAs such as BACE1-AS modulate amyloidogenic processes. Circular RNAs add further complexity to post-transcriptional regulation, though their roles remain an emerging research area.

Multi-omics and single-cell transcriptomics approaches have provided systems-level insights into disrupted gene regulatory networks, identifying hub genes and disease-associated pathways. These advances facilitate nuanced understanding of cellular heterogeneity and therapeutic target discovery.

Therapeutically, targeting gene regulation through epigenetic drugs, antisense oligonucleotides, and CRISPR-Cas9 gene editing represents a promising strategy for disease modification. While clinical trials report mixed outcomes, precision targeting tailored to individual gene regulatory profiles offers potential to improve efficacy and transform neurodegenerative disease treatment.

In sum, gene regulation—including transcriptional, epigenetic, and post-transcriptional mechanisms—is fundamental to neurodegenerative disease pathogenesis and presents actionable targets to alter disease trajectories.