Differential effects of overexpression of mutant huntingtin and TDP-43 in agouti-related protein neurons in the arcuate nucleus of the hypothalamus in mice

The spectrum of frontotemporal dementia/amyotrophic lateral sclerosis (FTD/ALS) and Huntington disease (HD) are fatal neurodegenerative disorders with no major disease-modifying therapies. Recent work has shown that the hallmark pathological proteins TAR DNA binding protein of 43 kDa (TDP-43) in FTD/ALS and mutant huntingtin (mHTT) in HD may be interlinked. Furthermore, these disorders share early features of altered metabolism and psychiatric symptoms that have been suggested to arise from pathology in the hypothalamus, an important brain region involved in the regulation of metabolism and emotions. Agouti-related protein (AgRP)-expressing neurons localised exclusively to the arcuate nucleus (ARC) of the hypothalamus are key modulators of body weight regulation and food seeking behaviour, and they have recently been implicated in anxiety- and anhedonic-like processes. The aim of this study was to investigate the effects of overexpression of TDP-43 or mHTT in AgRP-expressing neurons on metabolic, behavioral and neuropathological features in mice. Flex-switch adeno associated viral vectors expressing human wild-type TDP-43, mHTT or green fluorescent protein to serve as a control, were injected into male and female AgRP-Cre mice to target the ARC using stereotactic surgery. We demonstrate targeted overexpression of transgenes including formation of mHTT inclusions in the ARC of the hypothalamus. Overexpression of mHTT led to a significant reduction in AgRP fibres in the hypothalamus 21 weeks post-injection, as well as higher food consumption in female mice. Overexpression of TDP-43 did not lead to the development of any metabolic or behavioral phenotypes in the mice. Our data suggest that AgRP neurons in the ARC are protected from the toxic effects resulting from overexpression of TDP-43 whereas they display some sensitivity to mHTT overexpression resulting in mHTT inclusion formation, reduction in AgRP fibers and sex-specific effects on food consumption. Taken together, other hypothalamic neuronal populations may be more important for the development of non-motor features resulting from overexpression of TDP-43 and mHTT in the hypothalamus.