Elimination of huntingtin in the adult mouse leads to progressive behavioral deficits, bilateral thalamic calcification, and altered brain iron homeostasis

Abstract

Huntington’s Disease (HD) is an autosomal dominant progressive neurodegenerative disorder characterized by cognitive, behavioral and motor dysfunctions. HD is caused by a CAG repeat expansion in exon 1 of the HD gene that is translated into an expanded polyglutamine tract in the encoded protein, huntingtin (HTT). While the most significant neuropathology of HD occurs in the striatum, other brain regions are also affected and play an important role in HD pathology. To date there is no cure for HD, and recently strategies aiming at silencing HTT expression have been initiated as possible therapeutics for HD. However, the essential functions of HTT in the adult brain are currently unknown and hence the consequence of sustained suppression of HTT expression is unpredictable and can potentially be deleterious. Using the Cre-loxP system of recombination, we conditionally inactivated the mouse HD gene homologue at 3, 6 and 9 months of age. Here we show that elimination of Htt expression in the adult mouse results in behavioral deficits, progressive neuropathological changes including bilateral thalamic calcification, and altered brain iron homeostasis.

Effect of early embryonic deletion of huntingtin from pyramidal neurons on the development and long-term survival of neurons in cerebral cortex and striatum

“…Whether overall reductions in cortical and hippocampal neuron abundance occurred, or only in newborn hippocampal neurons, was not addressed. In a more extensive study (Dietrich et al, 2017), adult Hdh flox/ − mice carrying the tamoxifen-inducible CAAGG-CreER™ allele were injected with tamoxifen to induce global cre-mediated recombination and huntingtin elimination at 3, 6 or 9 months of age. A progressive rotarod impairment was evident by one month after tamoxifen treatment, and severe gait abnormalities, hind limb clasping on tail suspension, and resting tremors were seen by 16 months of age in all mice with deletion.…”

Striatal Projection Neurons Require Huntingtin for Synaptic Connectivity and Survival

“…One such therapeutic currently in clinical trials (IONIS-HTTRx, ClinicalTrials.org: NCT03342053) employs an intrathecal antisense oligonucleotide to non-selectively target the human HTT gene and reduce HTT expression in HD mutation carriers (Rodrigues and Wild, 2018). Although several studies in rodent and non-human primate models have shown that Htt knockdown in adult animals is not harmful (Wang et al, 2016a;McBride et al, 2011;Boudreau et al, 2009), one study found that Htt deletion in the adult mouse leads to brain atrophy, extensive reactive gliosis, and progressive motor symptoms (Dietrich et al, 2017). Our findings show that wild-type HTT plays an important role in both IP-SPNs and DP-SPNs, and preserving this function is critical for maintaining striatal health and function.…”

How the gene behind Huntington’s disease could be neutralized

“…Carroll despairingly cites two almost identical studies 6,7 in mice that gave radically different results. "Right now, we don't know enough, " he says.…”