Huntingtin-interacting protein 1

Huntingtin-interacting protein 1 (HIP1) is a 116 kDa protein involved in clathrin-mediated endocytosis and membrane trafficking (UniProt: O00291). It contains an ENTH domain that binds 3-phosphoinositides and plays roles in AMPA receptor trafficking, presynaptic function, and androgen receptor signaling. HIP1 may also regulate cell survival through receptor tyrosine kinase stabilization and can function as a proapoptotic factor through intrinsic apoptotic pathways.

HIP1 is primarily expressed in the central nervous system where it regulates synaptic transmission and neuronal vesicle dynamics (UniProt: O00291). Its role in NMDA-dependent receptor trafficking positions it at the intersection of excitatory neurotransmission and endosomal trafficking, processes critical for synaptic plasticity and neuronal homeostasis.

In Alzheimer's Disease, HIP1 is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls (Chaparral AD proteomics), with a mean log2 fold-change of −0.94. This reduction may impair clathrin-mediated endocytosis and AMPA receptor trafficking, potentially contributing to synaptic dysfunction and the cognitive decline characteristic of AD.