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Increased Activity-Dependent Bulk Endocytosis in Huntington's Disease Results From Huntingtin Haploinsufficiency
Han C G Tan1,2, Robyn L McAdam1, Andrew Morton1
1Centre for Discovery Brain Sciences, Hugh Robson Building, University of Edinburgh, Edinburgh, Scotland, UK.
Insights
Huntington's disease (HD) involves impaired synaptic vesicle recycling due to loss of wild-type huntingtin (htt) function. This dysfunction in activity-dependent bulk endocytosis (ADBE) in HD models suggests htt haploinsufficiency contributes to neurodegeneration.
Area of Science:
- Neuroscience
- Genetics
- Molecular Biology
Background:
- Huntington's disease (HD) is a progressive neurodegenerative disorder caused by CAG expansion in the HTT gene, leading to mutant huntingtin (htt) protein.
- While toxic gain-of-function from mutant htt is implicated, loss of wild-type htt function may also contribute to HD pathology.
- Previous studies identified disrupted synaptic vesicle protein recycling in striatal neurons of HD models, linked to wild-type htt loss during high neuronal activity.
Purpose of the Study:
- To investigate whether the observed synaptic recycling defect in HD models is associated with dysfunction in activity-dependent bulk endocytosis (ADBE).
- To determine the role of wild-type htt loss versus mutant htt gain-of-function in ADBE regulation during high neuronal activity.
Main Methods:
- Utilized HttQ140/Q140 and HttQ140/+ knockin mouse models of HD, mimicking preclinical and human disease states.
- Assessed ADBE by measuring evoked fluid-phase marker uptake in different neuronal subtypes under high activity conditions.
- Employed genetic manipulations, including htt depletion in wild-type neurons and selective removal of mutant htt, to dissect the contribution of htt alleles.
Main Results:
- Neurons from HttQ140/Q140 mice exhibited enhanced recruitment for ADBE, but no change in uptake extent, indicating a specific pathway dysfunction.
- This ADBE phenotype was confirmed to be due to loss of wild-type htt function, as htt depletion in wild-type neurons replicated the defect, and mutant htt removal did not rescue it.
- HttQ140/+ mice, modeling human HD, also showed increased activity-dependent ADBE triggering, suggesting htt haploinsufficiency is the primary driver.
Conclusions:
- Huntingtin (htt) haploinsufficiency, a loss of function of the wild-type allele, drives dysfunction in activity-dependent bulk endocytosis (ADBE) during high neuronal activity.
- This impaired ADBE represents a potential mechanism for circuit dysfunction and subsequent neurodegeneration observed in Huntington's disease.
- Targeting strategies that preserve wild-type htt function may be crucial for therapeutic interventions in HD.
Abstract:
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 HttQ140/Q140 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 HttQ140/Q140 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 HttQ140/Q140 neurons did not correct this dysfunction. Neurons from HttQ140/+ 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 HttQ140/+ 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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