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

## TL;DR

This study shows that the metabolic gene HKDC1 declines with age, leading to brain issues like memory loss and neuroinflammation in both mice and humans.

## Contribution

The study identifies HKDC1 as a novel metabolic gene linked to aging and neurodegeneration through chromatin and transcriptional changes.

## Key findings

- HKDC1 expression declines in humans and mouse models with cognitive decline and aging.
- Reduced HKDC1 leads to memory loss, anxiety, and mitochondrial dysfunction in mice.
- Chromatin changes block TFEB binding, causing HKDC1 downregulation and promoting neurodegeneration.

## Abstract

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.

Model showing decline in HKDC1 gene expression with aging. In a young cell, TFEB gets recruited to its binding sites on the HKDC1 promoter to upregulate HKDC1 expression, which interacts with mitochondria and stabilizes PINK1 to maintain mitochondrial health. With aging, the conformation of the HKDC1 promoter changes, which masks TFEB binding sites, thereby resulting in reduced TFEB binding on the HKDC1 promoter and downregulation of HKDC1 expression. This results in loss of PINK1 expression and mitochondrial dysregulation, which promotes senescence and neuroinflammation.