Transcriptional stalling by p16INK4a impairs mitochondrial bioenergetics and cognitive function in Alzheimer’s disease [ChIP-seq]

Yet, how neuronal p16INK4a contributes to neurodegeneration remains unclear, as prior research has largely focused on glial roles . Here, we show that p16INK4a is selectively upregulated in hippocampal granule neurons of AD patient brains and mouse models.

Mechanistically, p16INK4a directly binds to GTF2H1, a core subunit of the transcription factor IIH (TFIIH) complex, sterically hindering GTF2H1–RNA polymerase II assembly. This disruption causes genome-wide transcriptional stalling, with preferential downregulation of mitochondrial electron transport chain genes. Notably, p16INK4a overexpression stalls transcription of NDUFB9, a subunit of mitochondrial respiratory complex I, inducing mitochondrial dysfunction and neuronal energy deficits.