Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by an expanded CAG tract in the Huntingtin (HTT) gene, leading to toxic gains of function. HTT-lowering treatments are in clinical trials but risks imposed are unclear. Recent studies have reported on the consequences of widespread HTT loss in mice, where one group described early HTT loss leading to fatal pancreatitis, but later loss as benign. Another group reported no pancreatitis but found widespread neurological phenotypes including subcortical calcification. To better understand the liabilities of widespread HTT loss we knocked out Htt with two separate tamoxifen-inducible Cre lines. We find that loss of HTT at 2 months of age leads to progressive tremors and severe subcortical calcification at examination at 14 months of age but does not result in acute pancreatitis or histological changes in the pancreas. We additionally report that HTT loss is followed by sustained induction of circulating neurofilament light chain levels. These results confirm that global loss of HTT in mice is associated with pronounced risks, including progressive subcortical calcification and neurodegeneration.

Data and R scripts from the manuscript: Global huntingtin knockout in adult mice leads to fatal neurodegeneration that spares the pancreas (https://doi.org/10.26508/lsa.202402571)