Abstract
Synaptic dysfunction is a primary mechanism underlying Huntington disease (HD) progression. This study investigated changes in synaptic vesicle glycoprotein 2A (SV2A) density by means of 11C-UCB-J small-animal PET imaging in the central nervous system of mice with HD. Methods: Dynamic 11C-UCB-J small-animal PET imaging was performed at clinically relevant disease stages (at 3, 7, 10, and 16 mo) in the heterozygous knock-in Q175DN mouse model of HD and wild-type littermates (16-18 mice per genotype and time point). Cerebral 11C-UCB-J analyses were performed to assess genotypic differences during presymptomatic (3 mo) and symptomatic (7-16 mo) disease stages. 11C-UCB-J binding in the spinal cord was quantified at 16 mo. 3H-UCB-J autoradiography and SV2A immunofluorescence were performed postmortem in mouse and human brain tissues. Results:11C-UCB-J binding was lower in symptomatic heterozygous mice than in wild-type littermates in parallel with disease progression (7 and 10 mo: P < 0.01; 16 mo: P < 0.0001). Specific 11C-UCB-J binding was detectable in the spinal cord, with symptomatic heterozygous mice displaying a significant reduction (P < 0.0001). 3H-UCB-J autoradiography and SV2A immunofluorescence corroborated the invivo measurements demonstrating lower SV2A in heterozygous mice (P < 0.05). Finally, preliminary analysis of SV2A in the human brain postmortem suggested lower SV2A in HD gene carriers than in controls without dementia. Conclusion:11C-UCB-J PET detected SV2A deficits during symptomatic disease in heterozygous mice in both the brain and the spinal cord and therefore may be suitable as a novel marker of synaptic integrity widely distributed in the central nervous system. On clinical application, 11C-UCB-J PET imaging may have promise for SV2A measurement in patients with HD during disease progression and after disease-modifying therapeutic strategies.
Highlights
Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in exon 1 of the gene encoding the huntingtin protein [1], which leads to the expression of mutated huntingtin
synaptic vesicle glycoprotein 2A (SV2A) Density Decreases with HD Progression Longitudinal mean VT (IDIF) parametric maps of 11C-UCB-J at 7, 10, and 16M, displayed a broad cerebral reduction of 11C-UCB-J binding in symptomatic heterozygous mice compared to WT littermates (Figure 1A)
The reduced 11C-UCB-J uptake was not related to altered K1 values, suggesting the reduced binding was not reflecting a mere decrease in cerebral perfusion
Summary
Huntington’s Disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded polyglutamine repeat in exon 1 of the gene encoding the huntingtin protein [1], which leads to the expression of mutated huntingtin (mHTT). A growing body of evidence suggests that mHTT induces synaptic transmission dysfunction [4], synaptic dysfunction represents one of the main mechanisms underlying the progression of HD [5]. Alterations in pre-synaptic proteins, including regulators of endocytosis and exocytosis of synaptic vesicles such as synaptosomeassociated protein 25 and rabphilin 3A have been reported in both clinical [6,7] and preclinical [8,9,10] post-mortem studies. Previous studies have demonstrated mHTT abnormally associates with synaptic vesicles resulting in impaired synaptic function [11] and changes in synaptic proteins correlate with behavioural deficits [10], alterations in synaptic proteins may represent a candidate marker to monitor HD progression [12,13,14]. Given the current lack of effective treatment to prevent the disease or halt its progression, synaptic markers may play an important role in the development and evaluation of novel disease-modifying therapies throughout the entire central nervous system (CNS) [15]
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