Modification of ubiquitin C-terminal hydrolase L1 by reactive lipid species: role in neural regeneration and diseases of aging

Role of ubiquitin C-terminal hydrolase L1 (UCHL1) in brain function: Ubiquitin is used by a variety of cellular systems to tag proteins for transport to various organelles. There are a number of enzymes in the ubiquitin-proteasome pathway (UPP) that tag abnormally folded proteins with ubiquitin for transport to the proteasome for degradation. UCHL1 is a neuron-specific enzyme constituting over 1% of brain protein that can both ligate ubiquitin to proteins and hydrolyze ubiquitin (Ub) from proteins allowing for ubiquitin recycling (Setsuie and Wada, 2007). UCHL1 has several functions in neurons, including some that are specific for neuronal function (Figure 1). UCHL1 may tag abnormal unfolded proteins for transport to the proteasome as part of the neuronal UPP. Although it may play a role in the neuronal UPP, there are a variety of other deubiquitinases that are expressed in many other cell types such as UCHL3 that may serve this function in neurons. UCHL1 interacts with a number of cytoskeletal, axonal and synaptic proteins suggesting that it may have other neuron-specific functions. Mutations or deletion of UCHL1 produce prominent axonal pathology and white matter abnormalities in rodents, suggesting that UCHL1 is important in axonal and synaptic function in addition to the UPP (Kabuta et al., 2008). Furthermore, UCHL1 interacts with synaptic proteins suggesting that it may have a role in transporting synaptic vesicles to the plasma membrane central to neurotransmitter release. Inhibition of UCHL1 activity blocks long term potentiation in hippocampus (Gong et al., 2006). These and other observations suggest that UCHL1 is required for these neuron-specific functions rather than degradation of unfolded proteins. UCHL1 has been associated with the pathogenesis of a number of neurodegenerative diseases. A mutation in UCHL1 (Parkin 5) has been associated with familial Parkinson’s disease (PD). Furthermore, UCHL1 may be involved in the pathogenesis of Alzheimer’s disease (AD) (Setsuie and Wada, 2007). Oxidative modification and down-regulation of UCHL1 has been detected in idiopathic PD and AD brains (Choi et al., 2004). Genetic disruption of UCHL1 produces degeneration of motor neurons similar to those found in amyotrophic lateral sclerosis (ALS) (Bilguvar et al., 2013). These results suggest that UCHL1 activity may be important preserving axonal and synaptic function in a variety of disorders.