Silencing of the Metabolic Gene <scp>HKDC1</scp> Is Associated With Aging and Neurodegeneration in Mice and Humans

Increased life expectancy brought about by improved healthcare and lifestyle has heightened the challenge of neurodegenerative disorders like Alzheimer's disease (AD) and other age-related disorders. Neurodegeneration is known to be accompanied by loss of memory, changes in brain morphology, and neuroinflammation, and multiple factors contribute to the progression and pathogenesis of the condition. Of these factors, metabolic dysregulation is known to influence the process, but the precise mechanisms remain unexplored. In this study, we investigated the brain-specific role of the metabolic enzyme hexokinase domain-containing 1 (HKDC1) in neurodegeneration and observed that HKDC1 expression declines in humans with cognitive decline, which matches similar findings in mouse models of AD and aging. We observed age-dependent anxiety, compromised memory and learning, senescence, neuroinflammation, and mitochondrial function deficit in HKDC1-brain knockout mouse models. Furthermore, Chromatin immunoprecipitation (ChIP), RT-PCR, and Western blotting assays reveal that an age-related decline in HKDC1 expression stems from changes in chromatin conformation, which decrease the ability of transcription factor EB to regulate its transcription. These findings suggest an important role for the metabolic gene HKDC1 in the brain in relation to cognitive decline and the progression of neurodegeneration in mice and humans.