Silencing of the Metabolic Gene HKDC1 Is Associated With Aging and Neurodegeneration in Mice and Humans.

HKDC1 expression declines in humans with cognitive decline and in mouse models of Alzheimer's disease and aging.

• HKDC1 expression was examined in human brain tissue from individuals with varying degrees of cognitive decline.
• Similar declining expression patterns were observed in mouse models of AD and aging.
• The finding establishes a conserved association between HKDC1 silencing and neurodegeneration across species.

Brain-specific HKDC1 knockout mice exhibit age-dependent anxiety and compromised memory and learning.

• Behavioral phenotypes were assessed in HKDC1 brain knockout mouse models.
• Age-dependent anxiety was observed in the knockout animals.
• Memory and learning deficits were documented, consistent with a neurodegenerative phenotype.
• These behavioral changes were age-dependent, suggesting progressive deterioration.

HKDC1 brain knockout mice display cellular senescence and neuroinflammation.

• Senescence markers were elevated in the brains of HKDC1 knockout mice.
• Neuroinflammation was detected in the knockout animals, consistent with neurodegenerative pathology.
• These findings parallel known hallmarks of aging and Alzheimer's disease progression.

HKDC1 brain knockout mice show mitochondrial function deficits.

• Mitochondrial dysfunction was identified in brain-specific HKDC1 knockout mouse models.
• This finding links the metabolic enzyme HKDC1 to mitochondrial integrity in the brain.
• Mitochondrial dysfunction is a known contributor to neurodegeneration and metabolic dysregulation.

Age-related decline in HKDC1 expression is driven by chromatin conformation changes that reduce transcription factor EB (TFEB) binding and transcriptional regulation.

• Chromatin immunoprecipitation (ChIP) assays were used to assess chromatin accessibility at the HKDC1 locus.
• RT-PCR and Western blotting confirmed reduced HKDC1 transcript and protein levels.
• Age-related changes in chromatin conformation decreased the ability of transcription factor EB (TFEB) to regulate HKDC1 transcription.
• This epigenetic mechanism provides a molecular explanation for the observed age-dependent silencing of HKDC1.