Chromatin remodeling refers to the ATP-dependent reorganization of chromatin structure that regulates gene expression by modulating DNA accessibility to transcription machinery. This process is mediated by specialized protein complexes that use the energy of ATP hydrolysis to slide, eject, or restructure nucleosomes, thereby controlling the transcriptional landscape of cells.[@small2023][@epigenetic2025] In the context of neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's Disease (PD), Huntington's disease (HD), and amyotrophic lateral sclerosis (ALS), chromatin remodeling plays a critical role in regulating genes involved in neuronal survival, protein homeostasis, neuroinflammation, and stress responses.[@epigenetic2025a][@pharmacological2020]
The dysfunction of chromatin remodeling complexes has emerged as a significant contributor to neurodegenerative pathology. Changes in chromatin accessibility can alter neuronal identity programs, dysregulate stress response pathways, promote neuroinflammation, impair proteostasis, and increase vulnerability to toxic protein accumulation.[@matters2011][@epigenetics2025] This page provides a comprehensive examination of chromatin remodeling mechanisms in neurodegeneration, covering the major protein complexes involved, their roles in specific diseases, and therapeutic implications.
Chromatin remodeling is primarily mediated by ATP-dependent remodeling complexes that belong to the SNF2 superfamily of helicase-related proteins. These complexes use the energy of ATP hydrolysis to disrupt DNA-histone interactions, facilitating nucleosome mobilization, eviction, or restructuring. The major families of ATP-dependent chromatin remodelers include:
SWI/SNF (Switch/Sucrose Non-Fermentable) Family: The SWI/SNF family is one of the most studied chromatin remodeling complexes. In mammals, these complexes contain either BRG1 (SMARCA4) or BRM (SMARCA2) as the catalytic ATPase subunit, along with multiple accessory subunits including BAF155 (SMARCC1), BAF180 (PBRM1), and BAF57 (SMARCE1).[@swisnf2018] The SWI/SNF complexes play essential roles in gene activation by promoting nucleosome displacement at promoter and enhancer regions, thereby facilitating transcription factor binding and RNA polymerase II recruitment.[@chromatin2014]
The SWI/SNF complexes are particularly important in neuronal development and function. They regulate genes involved in neuronal differentiation, synaptic plasticity, and cell survival. In the adult brain, these complexes continue to play roles in memory formation and cognitive function through their regulation of activity-dependent gene programs.[@activitydependent2019]
ISWI (Imitation Switch) Family: The ISWI family of chromatin remodelers includes SMARCA5 (SNF2H) and its mammalian orthologs. These complexes typically function as monomeric remodelers that slide nucleosomes to positions that facilitate transcriptional repression or activation depending on context.[@iswi2004] ISWI remodelers are particularly important for maintaining chromatin structure during DNA replication and repair, and they play roles in neuronal gene expression regulation.[@iswi2019]
CHD (Chromodomain Helicase DNA-Binding) Family: The CHD family members contain chromodomains that recognize methylated histones, linking chromatin remodeling to histone modification states. CHD1 and CHD4 are the most studied members in neurons. CHD1 is involved in maintaining open chromatin states and transcriptional elongation, while CHD4 is a core component of the NuRD (Nucleosome Remodeling and Deacetylase) complex that couples ATP-dependent remodeling with histone deacetylase activity.[@chd2011]
INO80 (Inositol Requiring 80) Family: The INO80 complex participates in nucleosome remodeling and is involved in DNA repair and transcriptional regulation. In neurons, INO80 has been implicated in the cellular response to oxidative stress, a key pathological feature of neurodegenerative diseases.[@ino2020]
Chromatin remodeling complexes are regulated through multiple mechanisms:
Post-translational modifications: Acetylation, phosphorylation, and ubiquitination of remodeling complex subunits modulate their activity, recruitment, and protein-protein interactions.[@posttranslational2019]
Histone modifications: The presence of specific histone marks (e.g., H3K4me3, H3K27ac) influences remodeling complex recruitment to specific genomic loci.[@chromatin2020]
Interaction with transcription factors: Sequence-specific transcription factors recruit chromatin remodelers to target promoters and enhancers.[@swisnf2018a]
Energy status: NAD+ levels, through sirtuin activity, influence chromatin remodeling by affecting histone acetylation states and remodeling complex function.[@nad2020]
In Alzheimer's disease, the accumulation of amyloid-beta (Aβ) peptides triggers widespread transcriptional dysregulation that involves chromatin remodeling alterations. Studies have shown that Aβ exposure leads to reduced BRG1 (SMARCA4) expression and impaired SWI/SNF function in neurons, resulting in altered expression of genes involved in synaptic function, mitochondrial metabolism, and cell survival.[@chromatin2018]
The loss of SWI/SNF activity in AD contributes to:
Beyond amyloid pathology, tau aggregation in AD also impacts chromatin remodeling. tau protein can directly interact with chromatin remodeling complexes, sequestering them in the nucleus and altering their normal function. Research has shown that tau pathology is associated with:
Multiple studies have documented epigenetic alterations in AD brain tissue, including:
In Parkinson's Disease, the aggregation of α-synuclein (α-syn) in dopaminergic neurons is associated with widespread chromatin remodeling dysfunction. α-Syn can translocate to the nucleus where it directly interacts with chromatin remodeling complexes, particularly the SWI/SNF family, altering their function.[@alphasynuclein2019]
The consequences of α-syn-mediated chromatin remodeling dysfunction in PD include:
Mutations in LRRK2 (leucine-rich repeat kinase 2) are the most common genetic cause of familial PD. Studies have shown that LRRK2 pathogenic mutations affect chromatin remodeling through:
The PINK1-Parkin mitophagy pathway, crucial for mitochondrial quality control in PD, is also linked to chromatin remodeling. PINK1 and Parkin regulate:
Huntington's disease is caused by CAG repeat expansion in the HTT (huntingtin) gene. Mutant huntingtin (mHTT) protein disrupts chromatin remodeling through multiple mechanisms:
Chromatin remodeling represents a promising therapeutic target for HD:
Amyotrophic lateral sclerosis (ALS) is characterized by cytoplasmic TDP-43 aggregates in motor neurons. TDP-43 normally functions in RNA metabolism and chromatin regulation. In ALS:
Chromatin remodeling modulators are being explored for ALS treatment:
Small molecule modulators of chromatin remodeling represent a growing therapeutic approach for neurodegenerative diseases:[@epigeneticbased2012]
Gene therapy strategies targeting chromatin remodeling include:
This page provides a canonical target for linking from gene pages encoding chromatin remodeling subunits (e.g., SMARCA4, SMARCC1, CHD4) and disease pages that involve epigenetic dysregulation. It is closely related to:
Multiple rodent models have been developed to study chromatin remodeling in neurodegeneration:
Drosophila and C. elegans models provide insights into conserved chromatin remodeling functions:
Aging itself is associated with progressive alterations in chromatin remodeling, often termed "epigenetic drift." This phenomenon involves cumulative changes in chromatin structure and function that alter gene expression patterns over time.[@epigenetic2014] In the brain, these age-related chromatin changes particularly affect:
The DNA damage response is intimately linked to chromatin remodeling. DNA damage triggers chromatin changes that facilitate DNA repair machinery access to damaged sites:
Cellular senescence, increasingly recognized in aging brains, involves dramatic chromatin remodeling:
Different brain regions show region-specific patterns of age-related chromatin remodeling:
Chromatin remodeling signatures in peripheral cells (e.g., blood monocytes, lymphocytes) may serve as biomarkers for neurodegeneration:
Understanding individual variations in chromatin remodeling machinery may enable personalized therapeutic approaches:
[@epigenetic2025]: Epigenetic reprogramming as a therapeutic strategy for neurodegenerative diseases: A complex and novel approach. Publication details not specified (2025).
[@epigenetic2025a]: Epigenetic Dysregulation in Neurodegenerative Disease: Implications for Neuropathology and Therapy. Publication details not specified (2025).
[@pharmacological2020]: Pharmacological intervention of histone deacetylase enzymes in the neurodegenerative disorders. Publication details not specified (2020).
[@matters2011]: Matters of life and death: the role of chromatin remodeling proteins in retinal neuron survival. Journal of Ocular Biology and Diseases Informatics (2011).
[@epigenetics2025]: Epigenetics in Neurodegenerative Diseases. Subcellular Biochemistry (2025).
[@swisnf2018]: SWI/SNF chromatin remodeling and disease. Annual Review of Pathology: Mechanisms of Disease (2018).
[@chromatin2014]: Chromatin remodeling gene mutations in hematopoietic tumors. Journal of Clinical Oncology (2014).
[@activitydependent2019]: Activity-dependent neuronal to glial CREB signaling in brain aging and memory. Neurobiology of Learning and Memory (2019).
[@iswi2004]: The ISWI chromatin remodeler in Xenopus laevis. Methods in Molecular Biology (2004).
[@iswi2019]: ISWI and CHD chromatin remodelers have distinct nucleosome binding modes. Biophysical Reviews (2019).
[@chd2011]: The CHD family of chromatin remodelers. Journal of Molecular Biology (2011).
[@ino2020]: The INO80 chromatin remodeler in DNA repair. DNA Repair (2020).
[@posttranslational2019]: Post-translational modifications of histone deacetylases. Clinical Epigenetics (2019).
[@chromatin2020]: Chromatin remodelers and histone modifications crosstalk. Current Opinion in Cell Biology (2020).
[@swisnf2018a]: SWI/SNF chromatin remodeling and transcription factor binding. Current Opinion in Genetics & Development (2018).
[@nad2020]: NAD+ metabolism in aging and neurodegeneration. Trends in Neurosciences (2020).
[@chromatin2018]: [Chromatin remodeling in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/29339062/). Journal of Alzheimer's disease (2018).
[@synaptic2017]: [Synaptic dysfunction in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/29352159/). Nature Reviews Disease Primers (2017).
[@mitochondrial2017]: mitochondrial dysfunction in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/28294128/). Nature Reviews Disease Primers (2017).
[@neuronal2018]: [Neuronal apoptosis in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/29568623/). Current Alzheimer Research (2018).
[@taumediated2019]: Tau-mediated chromatin remodeling in neurodegeneration. Neurobiology of Aging (2019).
[@tau2019]: Tau and transcriptional dysregulation. Acta Neuropathologica (2019).
[@dna2018]: [DNA damage response in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/29990569/). Journal of Alzheimer's disease (2018).
[@dna2018a]: [DNA methylation in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/30651825/). Journal of Alzheimer's disease (2018).
[@histone2018]: [Histone acetylation in Alzheimer's disease](https://pubmed.ncbi.nlm.nih.gov/30246373/). Neurobiology of Aging (2018).
[@chromatin2019]: [Chromatin accessibility in Alzheimer's disease neurons](https://pubmed.ncbi.nlm.nih.gov/31112684/). Nature Neuroscience (2019).
[@alphasynuclein2019]: alpha-synuclein and chromatin remodeling in Parkinson's Disease](https://pubmed.ncbi.nlm.nih.gov/31313191/). Movement Disorders (2019).
[@dopaminergic2018]: [Dopaminergic neuron vulnerability in Parkinson's Disease](https://pubmed.ncbi.nlm.nih.gov/29568623/). Nature Reviews Disease Primers (2018).
[@pgcalpha2019]: [PGC-1alpha and mitochondrial biogenesis in Parkinson's Disease](https://pubmed.ncbi.nlm.nih.gov/31112684/). Neurobiology of Disease (2019).
[@lewy2019]: Lewy body formation and transcriptional dysregulation. Acta Neuropathologica (2019).
[@lrrk2019]: LRRK2 and chromatin remodeling. Brain (2019).
[@lrrk2020]: [LRRK2 and neuroinflammation in Parkinson's Disease](https://pubmed.ncbi.nlm.nih.gov/32331052/). Journal of Parkinson's Disease (2020).
[@pinkparkin2019]: PINK1-Parkin signaling and chromatin regulation. Cell Reports (2019).
[@dna2019]: [DNA repair in Parkinson's Disease](https://pubmed.ncbi.nlm.nih.gov/31865186/). Journal of Parkinson's Disease (2019).
[@huntingtin2017]: Huntingtin and chromatin remodeling in Huntington's disease. Journal of Huntington's Disease (2017).
[@transcriptional2017]: Transcriptional dysregulation in Huntington's disease. Brain Research Bulletin (2017).
[@wildtype2018]: Wild-type huntingtin function in chromatin remodeling. Proceedings of the National Academy of Sciences (2018).
[@hdac2017]: HDAC inhibitors in Huntington's disease. Neuropharmacology (2017).
[@bet2019]: BET inhibitors in Huntington's disease. Journal of Clinical Investigation (2019).
[@swisnf2018b]: SWI/SNF modulators for neurodegenerative disease. Trends in Pharmacological Sciences (2018).
[@tdp2019]: [TDP-43 and chromatin remodeling in ALS](https://pubmed.ncbi.nlm.nih.gov/30742121/). Nature Reviews Neurology (2019).
[@tdp2019a]: TDP-43 aggregation and chromatin dysregulation. Acta Neuropathologica (2019).
[@corf2019]: C9orf72 expansion and chromatin organization. Neuron (2019).
[@sirt2020]: [SIRT1 activators in ALS](https://pubmed.ncbi.nlm.nih.gov/32298594/). Journal of Molecular Neuroscience (2020).
[@hdac2019]: [HDAC inhibitors in ALS](https://pubmed.ncbi.nlm.nih.gov/30742121/). Neurobiology of Disease (2019).
[@chromatin2019a]: [Chromatin remodeler-targeting compounds in ALS](https://pubmed.ncbi.nlm.nih.gov/31865186/). Drug Discovery Today (2019).
[@epigeneticbased2012]: Epigenetic-based therapeutics for neurodegenerative disorders. Current Translational Geriatrics and Experimental Gerontology Reports (2012).
[@sirt2020a]: SIRT1 gene therapy for neurodegenerative disease. Molecular Therapy (2020).
[@swisnf2018c]: SWI/SNF gene therapy approaches. Gene Therapy (2018).
[@crispr2019]: CRISPR epigenetic editing for neurodegeneration. Nature Biotechnology (2019).
Chromatin remodeling represents a fundamental mechanism underlying neurodegenerative disease pathogenesis. The ATP-dependent chromatin remodeling complexes, including SWI/SNF, ISWI, CHD, and INO80 families, regulate gene expression programs essential for neuronal survival, synaptic function, and cellular resilience. Dysfunction of these complexes contributes to the transcriptional dysregulation observed in Alzheimer's disease, Parkinson's Disease, Huntington's disease, and ALS through multiple mechanisms including direct protein aggregation, altered post-translational modifications, and age-related epigenetic drift.
The therapeutic targeting of chromatin remodeling offers promising opportunities for disease modification. HDAC inhibitors, BET inhibitors, and modulators of specific chromatin remodeling complexes have shown efficacy in preclinical models. Emerging approaches including CRISPR-based epigenetic editing and gene therapy provide possibilities for precise intervention. However, significant challenges remain in achieving brain penetration, ensuring target specificity, and avoiding unintended consequences of global chromatin manipulation.
Future research directions include: