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Published on: March 11, 2020
Altered PDE10A expression detectable early before symptomatic onset in Huntington's disease
Flavia Niccolini1, Salman Haider2, Tiago Reis Marques3
11 Neurodegeneration Imaging Group, Department of Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK 2 Division of Brain Sciences, Department of Medicine, Imperial College London, London, UK.
Early detection of Huntington's disease (HD) may be possible by measuring phosphodiesterase 10A (PDE10A) levels. Changes in PDE10A in the brain correlate with the likelihood of developing HD symptoms, offering new therapeutic targets.
Area of Science:
- Neuroscience
- Biomarkers
- Pharmacology
Background:
- Huntington's disease (HD) is a neurodegenerative disorder with urgent need for early biomarkers and therapies.
- Mutant huntingtin in HD affects striatal medium spiny neurons expressing phosphodiesterase 10A (PDE10A).
- PDE10A regulates striatal output and neuronal survival, making it a potential therapeutic target.
Purpose of the Study:
- To assess in vivo PDE10A expression in early premanifest Huntington's disease gene carriers.
- To investigate the relationship between PDE10A levels and the probability of symptomatic onset.
- To identify novel pathophysiological mechanisms and therapeutic targets for HD.
Main Methods:
- Combined positron emission tomography (PET) and multimodal magnetic resonance imaging (MRI).
- Assessed PDE10A expression in 12 early premanifest HD gene carriers and matched controls.
- Utilized connectivity-based analysis to examine PDE10A distribution.
Main Results:
- Demonstrated bidirectional changes in PDE10A expression in premanifest HD gene carriers.
- Observed decreased PDE10A in striatum/pallidum and increased PDE10A in motor thalamic nuclei compared to controls.
- Found a ratio of PDE10A expression in thalamic nuclei to striatum strongly correlated with symptomatic conversion probability.
Conclusions:
- PDE10A expression changes are an early pathophysiological mechanism in Huntington's disease.
- PDE10A represents a novel, earliest biomarker for HD.
- Findings support PDE10A as a therapeutic target for promoting neuronal survival and improving outcomes in HD.
