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Ubiquitin pathway (UBE3A, PARK2, RFWD2 and FBXO40)

Ubiquitin Proteasome System PMID 19597829

The genes UBE3A, PARK2, RFWD2 and FBXO40 are a part of the Ubiquitin pathway and have been implicated as genes that may possibly confer susceptibility to ASD through genome wide CNV association studies. Ubiquitination is a post-translational modification that can alter protein function and target proteins for proteosome degradation. This system can regulate synaptic attributes, including neurotransmitter release, synaptic vesicle recycling in pre-synaptic terminals, dynamic changes in dendritic spines, and post-synaptic density. All four of the genes are ubiquitin-protein ligases. UBE3A is the most studied of the four in relation to autism and PARK2 mutations have been linked to autosomal reccessive juvenile Parkinson's disease. 1

Ubiquitin may be responsible for the turnover of synaptic components such as neuronal cell-adhesion molecules in a process that involves regulation of activity-dependent synaptic plasticity. Other ubiquitin related genes such as NHLRC1, UBR, CUL4B, BRwD3, and HUWE1 are involved in human neurological diseases. Mutations in the last three and UBE2A cause syndromes including intellectual disability.1

Ubiquitination Process

In this process, a small protein ubiquitin is covalently attached to lysine residues on the target protein via peptide bonds. Additional ubiquitin monomers are often added onto the first ubiquitin to form a chain of 4-7 ubiquitin monomers. Ubiquitin with the attached ubiquitin is then guided to the protease complex 26S proteasome, located in the nucleus and cytoplasm of mammalian cells, where the protein is degraded. Ubiquitination targets oxidized, mutant, or misfolded proteins for general proteolytic destruction. Ubiquitination also allows for tightly controlled and specific destruction of proteins involved in development and differentiation, cell cycle progression, circadian rhythms, apoptosis, and other biological processes. 2

Alteration of the ubiquitin proteasome system(UPS) or mutations in the target proteins result in signaling abnormalities in the brain. A dysregulated UPS can also perturb DNA replication and mitotic control mechanisms to lead to genomic instability. In neurodegenerative diseases caused by mutant protein expression, the amount of mutant proteins can overwhelm the UPS and indirectly contribute to the disease process. 2


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1. Glessner JT, et. al. Autism genome-wide copy number variation reveals ubiquitin and neuronal genes.Nature. 2009 May 28;459(7246):569-73 PMID 19404257

2. Lehman, NL. The ubiquitin proteasome system in neuropathology. Acta Neuropathol (2009) 118:329–347 PMID 19597829