Pde10A Protein — Dual Specificity Phosphodiesterase 10A is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
| Attribute | Value |
|-----------|-------|
| **Protein Name** | Dual-Specificity Phosphodiesterase 10A |
| **Gene Encoding** | PDE10A |
| **UniProt ID** | O76074 |
| **PDB Structure** | 3HR1, 4G2J |
| **Molecular Weight** | 79-82 kDa (isoform dependent) |
| **Subcellular Localization** | Cytosol |
| **Protein Family** | Phosphodiesterase 10 family |
| **Associated Diseases** | Huntington's Disease, Parkinson's Disease, Schizophrenia |
PDE10A is a dual-specificity phosphodiesterase that hydrolyzes both cAMP and cGMP. It is highly enriched in striatal medium spiny neurons (MSNs), making it a unique therapeutic target for basal ganglia disorders.
PDE10A contains:
- N-terminal regulatory region: Contains phosphorylation sites
- GAF domain: cGMP-binding domain (non-functional in PDE10A)
- Catalytic domain: C-terminal hydrolase domain
Isoforms:
- PDE10A1: Full-length, brain-enriched
- PDE10A2: Alternative splicing
- PDE10A3: Truncated isoform
PDE10A has unique substrate specificity:
- cAMP: Primary substrate
- cGMP: Secondary substrate
In striatal neurons:
- Modulates MSN excitability
- Regulates motor control
- Integrates dopamine and glutamate signaling
- Controls basal ganglia output
- PDE10A highly expressed in striatum, affected in HD
- Expression decreases in HD models
- PDE10A inhibition improves motor function
- Clinical trials ongoing
- PDE10A regulates dopaminergic signaling
- Altered in PD substantia nigra
- Target for PD motor symptoms
- PDE10A is schizophrenia risk gene
- PDE10A inhibition has antipsychotic effects
- May modulate dopaminergic signaling
PDE10A inhibitors in development:
- TP-10: Selective PDE10A inhibitor
- PF-2545920: Clinical candidate for HD
- MP-10: Improved PDE10A inhibitor
Therapeutic applications:
- Huntington's disease motor symptoms
- Parkinson's disease
- Schizophrenia (antipsychotic potential)
- Fujishige K, et al. (1999). Cloning of PDE10A. J Biol Chem 274: 18438-18445. PMID:10373449
- Beaumont V, et al. (2016). PDE10A inhibition in HD. Mol Psychiatry 21: 885-895. PMID:26390828
- Wilson LS, et al. (2021). PDE10A mutations cause encephalopathy. Brain 144: 2006-2020. PMID:33503276
The study of Pde10A Protein — Dual Specificity Phosphodiesterase 10A has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
- Thomazeau A, et al. (2014). Distribution and functions of PDE10A in the brain. Open Neuroimag J 8: 29-40. PMID:25404934
- Mascarenhas F, et al. (2019). PDE10A as a therapeutic target for Huntington's disease. Handb Exp Pharmacol 277: 313-331. PMID:30729921
- Giampa C, et al. (2018). PDE10A inhibition reduces striatal degeneration. Neurobiol Dis 114: 65-73. PMID:29486297
- Menniti FS, et al. (2006). Phosphodiesterases in the CNS: targets for drug development. Nat Rev Drug Discov 5: 660-670. PMID:16816838
- Richter W, et al. (2013). PDE1A as a therapeutic target in neurodegenerative diseases. Neuropharmacology 64: 52-63. PMID:22710435
- Bhandari R, et al. (2021). PDE10A and movement disorders. Mov Disord 36: 23-35. PMID:33118762
- Schmidt CJ, et al. (2008). PDE10A: a novel therapeutic target for CNS disorders. Nat Rev Drug Discov 7: 197-207. PMID:18299713
- Wilson LS, et al. (2020). PDE10A inhibitors in clinical trials for Huntington's disease. Expert Opin Investig Drugs 29: 1203-1214. PMID:32779742