DFFA is a human gene whose product the DFFA gene encodes DFF45 (DNA Fragmentation Factor 45 kDa), also known as ICAD (Inhibitor of Caspase-Activated DNase). DFF45 is a 331-amino acid protein that serves as a chaperone and specific inhibitor for DFF40. Variants in DFFA have been implicated in Alzheimer's Disease (AD), Parkinson's Disease (PD), Stroke and Brain Ischemia. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
DFFA is a human gene whose product the DFFA gene encodes DFF45 (DNA Fragmentation Factor 45 kDa), also known as ICAD (Inhibitor of Caspase-Activated DNase). DFF45 is a 331-amino acid protein that serves as a chaperone and specific inhibitor for DFF40. Variants in DFFA have been implicated in Alzheimer's Disease (AD), Parkinson's Disease (PD), Stroke and Brain Ischemia. This page covers the gene's normal function, disease associations, expression patterns, and key research findings relevant to neurodegeneration.
DFFA encodes the 45 kDa subunit of DNA fragmentation factor (DFF), also known as inhibitor of CAD (ICAD). DFF45 acts as an inhibitor of DFF40 (CAD - Caspase-Activated DNase). Upon caspase-3 cleavage during [apoptosis](/entities/apoptosis), DFF45 is inactivated, allowing DFF40 to translocate to the nucleus and execute DNA fragmentation [1](https://pubmed.ncbi.nlm.nih.gov/10625666/). While DFF is primarily studied in apoptosis, its regulation is critically relevant to neuronal cell death in neurodegenerative diseases [2](https://pubmed.ncbi.nlm.nih.gov/10328735/).
Normal Function
The DFFA gene encodes DFF45 (DNA Fragmentation Factor 45 kDa), also known as ICAD (Inhibitor of Caspase-Activated DNase). DFF45 is a 331-amino acid protein that serves as a chaperone and specific inhibitor for DFF40.
Mechanism:
DFF45 binds to DFF40 in the cytoplasm, preventing its nuclease activity
During apoptosis, caspase-3 cleaves DFF45 at specific aspartic acid residues
Cleaved DFF45 releases active DFF40, which translocates to the nucleus
DFF40 exhibits endonuclease activity, producing characteristic DNA ladders [1](https://pubmed.ncbi.nlm.nih.gov/10625666/)
Non-Apoptotic Functions:
ICAD acts as a transcriptional co-activator for certain genes
The DFF complex may participate in DNA repair pathways
Disease Associations
Alzheimer's Disease (AD)
In Alzheimer's disease, DFFA/DFF45 plays a complex role in neuronal death:
Increased DFF45 cleavage in AD brain tissue correlates with neuronal loss [3](https://pubmed.ncbi.nlm.nih.gov/10625666/)
Caspase-3 activation is elevated in vulnerable brain regions
DFF-mediated DNA fragmentation contributes to cholinergic neuron death [4](https://pubmed.ncbi.nlm.nih.gov/PMC2736157/)
Parkinson's Disease (PD)
In Parkinson's disease, DFFA contributes to dopaminergic neuron death:
6-OHDA and MPTP models show increased DFF45 cleavage in the substantia nigra
Mitochondrial dysfunction leads to caspase activation and DFF40 activation [5](https://pubmed.ncbi.nlm.nih.gov/12547824/)
Stroke and Brain Ischemia
DFFA is particularly relevant to ischemic brain injury:
Cerebral ischemia rapidly activates caspase-3 and DFF in vulnerable [neurons](/entities/neurons)
DFF45 knockout mice show reduced DNA fragmentation after focal cerebral ischemia [6](https://pubmed.ncbi.nlm.nih.gov/11751808/)
Amyotrophic Lateral Sclerosis (ALS)
In ALS, DFFA contributes to motor neuron death:
Spinal motor neurons from ALS patients show evidence of DFF activation
SOD1 mutations enhance caspase activation and DFF-mediated DNA fragmentation
Expression Pattern
DFFA is expressed throughout the brain:
[Cortex](/brain-regions/cortex): Pyramidal neurons in layers III and V