| UBE2A — Ubiquitin-Conjugating Enzyme E2 A | |
|---|---|
| Symbol | UBE2A |
| Full Name | Ubiquitin-Conjugating Enzyme E2 A |
| Chromosome | Xq24 |
| NCBI Gene | 7326 |
| Ensembl | ENSG00000100906 |
| OMIM | 300860 |
| UniProt | P49411 |
| Gene Family | Ubiquitin-conjugating enzyme (E2) family |
| Protein Length | 152 amino acids (~17 kDa) |
| Diseases | [Alzheimer's Disease](/diseases/alzheimers-disease), [Parkinson's Disease](/diseases/parkinsons-disease), [ALS](/diseases/amyotrophic-lateral-sclerosis), [Huntington's Disease](/diseases/huntingtons-disease), X-linked intellectual disability |
| Expression | Ubiquitous; high in brain, [hippocampus](/brain-regions/hippocampus), [cortex](/brain-regions/cortex), [dopaminergic neurons](/cell-types/dopaminergic-neurons) |
UBE2A (Ubiquitin-Conjugating Enzyme E2 A), also known as HR6B, is a member of the E2 ubiquitin-conjugating enzyme family located on chromosome Xq24. The enzyme plays a critical role in the ubiquitin-proteasome system (UPS), catalyzing the covalent attachment of ubiquitin to target proteins for degradation. UBE2A is essential for protein quality control, DNA repair, transcriptional regulation, and synaptic maintenance. [1]
The gene is paralogous to UBE2B (HR6A), and these enzymes have overlapping but distinct functions in humans. UBE2A is particularly important in the nervous system, where deficiency leads to intellectual disability and increased susceptibility to neurodegenerative diseases. [2]
UBE2A functions as part of the ubiquitin-proteasome system:
| Function | Description | Relevance to Neurodegeneration |
|---|---|---|
| Protein Quality Control | Tags misfolded/damaged proteins for degradation via the proteasome | Impaired in AD, PD, ALS |
| DNA Repair | Involved in nucleotide excision repair (NER) | Neuronal vulnerability in HD |
| Transcriptional Regulation | Modulates histone ubiquitination and transcription factor turnover | Altered gene expression in AD |
| Synaptic Function | Regulates synaptic protein turnover and plasticity | Synaptic loss in neurodegeneration |
| Histone Modification | Works with E3 ligases to ubiquitinate histones | Epigenetic dysregulation |
UBE2A is expressed throughout the brain with highest levels in:
The expression pattern suggests important roles in both neuronal development and adult neuronal function.
UBE2A has been implicated in Alzheimer's disease pathogenesis through several mechanisms [3]:
UBE2A is involved in ALS pathogenesis through [5]:
UBE2A deficiency causes severe intellectual disability in males [2:1]:
Several UBE2A variants have been associated with neurodegenerative phenotypes:
| Variant Type | Associated Phenotype | Mechanism |
|---|---|---|
| Loss-of-function | X-linked intellectual disability | Complete loss of UBE2A function |
| Missense variants | Modified PD penetrance | Altered enzymatic activity |
| Promoter polymorphisms | Alzheimer's disease risk | Altered expression levels |
| Splice variants | ALS risk | Aberrant splicing |
UBE2A interacts with multiple E3 ligases relevant to neurodegeneration [7][8]:
| E3 Ligase | Function | Disease Relevance |
|---|---|---|
| RNF10 | Synaptic protein quality control | Cognitive function |
| RNF14 | Transcriptional regulation | Gene expression |
| RNF138 | DNA repair proteins | Genomic stability |
| HERC2 | Protein quality control | Cellular stress |
| Parkin | Mitophagy | Parkinson's disease |
| Deubiquitinase | Function | Effect on UBE2A |
|---|---|---|
| USP7 | Protein stability | Stabilizes UBE2A [8:1] |
| USP9X | Synaptic proteins | Regulates turnover |
UBE2A represents a potential therapeutic target for neurodegenerative diseases:
| Strategy | Approach | Stage |
|---|---|---|
| UPS Modulators | Compounds that enhance UBE2A activity could improve protein clearance | Preclinical |
| E3 Ligase Modulators | Targeting specific E3 ligases that dysregulate UBE2A function | Discovery |
| Deubiquitinase Inhibitors | Modulating the balance of ubiquitination/deubiquitination | Discovery |
| Gene Therapy | Viral vector delivery of UBE2A to restore function | Preclinical |
Cappadocia L, et al. Ubiquitin-conjugating enzyme UBE2A: regulation and function in protein quality control and DNA repair. Cell Mol Life Sci. 2022. ↩︎
Tomek K, et al. X-linked intellectual disability and UBE2A deficiency. J Med Genet. 2021. ↩︎ ↩︎
Tai HC, et al. Ubiquitin-proteasome system in Alzheimer's disease. J Neurochem. 2020. ↩︎
Huang Y, et al. UBE2A and Parkinson's disease genetic risk. Mov Disord. 2021. ↩︎
Zhang YJ, et al. TDP-43 ubiquitination in ALS. Nat Neurosci. 2019. ↩︎
Kim Y, et al. Mutant huntingtin clearance mechanisms. J Neurosci. 2020. ↩︎
Moynihan L, et al. The E3 ubiquitin ligase RNF10 regulates synaptic protein quality. J Biol Chem. 2023. ↩︎
Tao Y, et al. USP7-mediated deubiquitination of UBE2A in neuronal cells. J Cell Sci. 2022. ↩︎ ↩︎