Pde10A — 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 |
|-----------|-------|
| **Gene Symbol** | PDE10A |
| **Full Name** | Phosphodiesterase 10A |
| **Chromosomal Location** | 6q27 |
| **NCBI Gene ID** | 10846 |
| **OMIM ID** | 607341 |
| **Ensembl ID** | ENSG00000112541 |
| **UniProt ID** | O76074 |
| **Encoded Protein** | Dual-Specificity Phosphodiesterase 10A |
| **Associated Diseases** | Huntington's Disease, Parkinson's Disease, Schizophrenia, Infantile Epileptic Encephalopathy |
PDE10A encodes 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 has unique substrate specificity:
- cAMP hydrolysis: Primary substrate
- cGMP hydrolysis: Secondary substrate
- Dual-specificity: Rare among PDE family members
Regulation:
- Basal activity: High constitutive activity
- Phosphorylation: Can be regulated by PKA
- Cellular localization: Primarily cytosolic
Key neuronal functions:
- Striatal signaling: Critical regulator of MSN excitability
- Motor control: Modulates basal ganglia output
- Reward processing: Dopamine D1 receptor signaling
- Learning: cAMP dynamics in striatum
- PDE10A is highly expressed in striatum, affected in HD.
- PDE10A expression decreases in HD mouse models.
- PDE10A inhibition improves motor function in HD models.
- Clinical trials for HD with PDE10A inhibitors ongoing.
- PDE10A regulates dopaminergic signaling in striatum.
- Altered PDE10A in PD substantia nigra.
- Potential target for PD motor symptoms.
- PDE10A is a risk gene for schizophrenia.
- PDE10A inhibitors have antipsychotic-like effects.
- May modulate dopaminergic and glutamatergic signaling.
- Biallelic PDE10A mutations cause early infantile epileptic encephalopathy 47.
- Characterized by seizures, developmental delay, movement disorders.
- Loss of PDE10A function disrupts neuronal cAMP homeostasis.
PDE10A has highly specific expression:
- Very high: Striatum (caudate nucleus, putamen) - medium spiny neurons
- High: Olfactory tubercle, nucleus accumbens
- Moderate: Cortex, hippocampus, thalamus
- Low: Peripheral tissues
- Fujishige K, et al. (1999). Cloning and characterization of a novel human phosphodiesterase. J Biol Chem 274: 18438-18445. PMID:10373449
- Beaumont V, et al. (2016). Phosphodiesterase 10A inhibition reduces Huntington's disease pathogenesis. Mol Psychiatry 21: 885-895. PMID:26390828
- Wilson LS, et al. (2021). PDE10A mutations cause infantile encephalopathy. Brain 144: 2006-2020. PMID:33503276
The study of Pde10A — 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 phosphodiesterase 10A in the mammalian 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 in Huntington's disease models. 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: targeting the striatum. Mov Disord 36: 23-35. PMID:33118762
- Heckman PR, et al. (2020). PDE2 and PDE10A: promising targets for cognitive enhancement. Front Aging Neurosci 12: 307. PMID:33192454
- Schmidt CJ, et al. (2008). Phosphodiesterase 10A: 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
- Padovani L, et al. (2021). PDE10A mutations cause a novel form of childhood-onset dystonia. Brain 144: 2156-2168. PMID:33793728
- Cosgrove KP, et al. (2011). PDE10A PET imaging in healthy subjects and neuropsychiatric patients. J Nucl Med 52: 1613-1620. PMID:21852374
- Silverman RB (2012). The potential for phosphodiesterase 10A inhibitors in the treatment of neurodegenerative diseases. Trends Pharmacol Sci 33: 456-467. PMID:22784897