Neuroanatomical distribution of endogenous huntingtin and its immunohistochemical relationships with STB/HAP1 in the adult mouse brain and spinal cord.

Huntingtin-associated protein 1 (HAP1) is an essential constituent of the stigmoid body (STB) and is known as a neuroprotective interactor with causal agents for several neurodegenerative disorders, including huntingtin (HTT) in Huntington's disease. Previous in vitro studies showed that compared to normal HTT, STB/HAP1 exhibited a higher binding affinity for mutant HTT. The detailed in vivo relationships of STB/HAP1 with endogenous HTT, however, have not been clarified yet. This study examined the distribution of endogenous HTT and its relationships with STB/HAP1 in the adult mouse brain and spinal cord using light/fluorescence microscopy. Our results show that HTT immunoreactivity is highly distributed in the striatum, medial septal nucleus (MS), nucleus of the horizontal limb/ vertical limb of the diagonal band of Broca (HDB, VDB), substantia innominata basal part (SIB), pedunculopontine tegmental nucleus (PPTg), laterodorsal tegmental nucleus (LDTg), autonomic preganglionic neurons, and brainstem/spinal motoneurons. More than 90 % of HTT-immunoreactive (ir) neurons contain STB/HAP1 immunoreactivity in MS, VBD/HDB, SIB, PPTg, LDTg, and autonomic preganglionic nuclei. HTT-ir neurons in the striatal and motor nuclei, however, do not exhibit HAP1 immunoreactivity. These suggest that due to the absence of STB/HAP1-protectivity, HTT-ir striatal/motor neurons are more vulnerable to neurodegeneration than other HAP1-expressing HTT neurons. Our current findings might provide a framework for elucidating the pathophysiological functions of endogenous HTT and HAP1 in the central nervous system.