Increased Activity-Dependent Bulk Endocytosis in Huntington’s Disease Results From Huntingtin Haploinsufficiency.

Publication date: Jun 01, 2025

Huntington’s disease (HD) is a life-limiting, progressive monogenic neurodegenerative disorder characterised by chorea, hypokinesis and psychosocial symptoms. HD is characterised by a variable CAG expansion in exon 1 of the HTT gene, which encodes the huntingtin (htt) protein. This expansion results in an extended polyglutamine tract, which is widely thought to confer a toxic gain of function on the protein that is responsible for disease progression. Most individuals with HD are heterozygous for this mutation, meaning that loss of wild-type htt function may also contribute to disease pathology. We previously identified that the recycling of synaptic vesicle proteins at the presynapse was specifically disrupted in striatal neurons from a preclinical model of HD, the Htt knockin mouse. This defect was only revealed during high activity and, notably, was due to loss of wild-type htt function. The dominant endocytosis mode at the presynapse during high activity is activity-dependent bulk endocytosis (ADBE). Therefore, we determined whether dysfunction in this pathway was linked to this recycling defect. We revealed that three independent neuronal subtypes derived from Htt mice displayed enhanced recruitment, but no change in the extent of ADBE via the evoked uptake of fluid phase markers. Importantly, this phenotype was due to a loss of wild-type htt function, since depletion of htt in Htt neurons mimicked the defect, and removal of mutant htt from Htt neurons did not correct this dysfunction. Neurons from Htt mice, which mimic the human condition, also displayed increased activity-dependent triggering of ADBE, suggesting that htt haploinsufficiency may be responsible. This was confirmed by the inability of zinc finger proteins that selectively target mutant htt to correct this defect in Htt neurons. Therefore, htt haploinsufficiency drives dysfunction in a key endocytosis mode that is dominant during high neuronal activity, providing a potential mechanism for circuit dysfunction that results in neurodegeneration in later life in HD.

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