Data From: Global huntingtin knockout in adult mice leads to fatal neurodegeneration that spares the pancreas

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.