Huntington disease is associated with the expansion of a polyglutamine tract, greater than 35 repeats, in the HD gene product huntingtin. HIP1 (huntingtin-interacting protein 1), a membrane-associated protein, binds specifically to the N-terminus of human huntingtin. HIP1 is ubiquitously expressed in different brain regions at low levels, and exhibits nearly identical subcellular fractionation as huntingtin. The huntingtin-HIP1 interaction is restricted to the brain and is inversely correlated to the polyglutamine length in the huntingtin, suggesting that loss of normal huntingtin-HIP1 interaction may compromise the membrane-cytoskeletal integrity in the brain. HIP1 contains an endocytic multidomain protein with a C-terminal Actin-binding domain, a central coiled-coil forming region and an N-terminal ENTH domain. HIP1 may be involved in vesicle trafficking; the structural integrity of HIP1 is crucial for maintenance of normal vesicle size in vivo. HIP12 is a non-proapoptotic member of the HIP gene family that is expressed in the brain and shares a similar subcellular distribution pattern with HIP1. However, HIP12 differs from HIP1 in its pattern of expression at both the mRNA and protein level. HIP12 does not directly interact with huntingtin but can interact with HIP1.