PEX5-related protein

PEX5L (PEX5-related protein) is an accessory subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels that regulates their cell-surface expression and cyclic nucleotide dependence (UniProt: Q8IYB4). The protein is a 626-amino-acid, ~70 kDa polypeptide expressed in human tissues. HCN channels are involved in neuronal excitability and synaptic transmission, processes central to brain function.

PEX5L has not been annotated with specific disease associations in UniProt, though its role in modulating ion channel function suggests potential relevance to neurological processes. The protein localizes across multiple subcellular compartments, as suggested by its detection across fractions in proteomic analyses.

In Alzheimer's Disease, PEX5L is down-regulated in post-mortem AD brain relative to age-matched controls (Chaparral AD proteomics). The mean log2 fold-change is −0.44, reflecting a modest but consistent reduction across two subcellular fractions in TMT-labeled proteomics analysis. This down-regulation may reflect altered HCN channel regulation in AD pathology, potentially impacting neuronal excitability in affected brain regions.