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. However, the detailed in vivo relationships of STB/HAP1 with endogenous HTT 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 motor neurons. More than 90% of HTT-immunoreactive (ir) neurons contain STB/HAP1 immunoreactivity in MS, VBD/HDB, SIB, PPTg, LDTg, and autonomic preganglionic nuclei. However, HTT-ir neurons in the striatal and motor nuclei lack HAP1 immunoreactivity. These suggest that due to the absence of STB/HAP1 protectivity, the 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.