ReviewLife and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia
Section snippets
Ubiquitin proteasome pathway (UPP) in normal brain function
In order to maintain brain function, neurons must survive for the life of the organism since neuronal mitosis is complete in most neurons by birth. This poses unique challenges for the neuron and requires efficient systems for maintaining cellular integrity, cellular repair and removing potential toxins from the cell (Ciechanover and Kwon, 2015, Jara et al., 2013). These toxins include abnormally folded or aggregated proteins (Haass and Selkoe, 2007). Neurodegenerative diseases such as
UPP and aging
In order to preserve the function and viability of the neuron throughout its lifespan, it is essential to degrade and remove abnormal potentially toxic proteins. In addition, neurons are unique in that they contain axons and dendrites that do not include all of the proteolytic components of the cell body. Thus, abnormal proteins located in axons and dendrites must be transported to the cell body for disposal by the proteasome and other systems such as the lysosome and autophagy (Yerbury et al.,
Interrelation between UPP dysfunction in ischemia, aging and neurodegenerative diseases
UPP dysfunction may play an important role in the aging neuron and may underlie the accumulation of abnormal proteins in neurodegenerative diseases. Epidemiological studies indicate that vascular risk factors, white matter hyper-intensities and strokes increase the incidence of cognitive impairment and AD (Jefferson et al., 2015, Nelson et al., 2016, Zlokovic, 2011). Hypertension, diabetes and hyperlipidemia are associated with small vessel cerebrovascular disease associated with micro
Role in neuronal function
UCHL1 is highly expressed in brain, composing >1% of brain protein and may play an important role in the neuronal UPP (Larsen et al., 1996). It is selectively expressed in neurons, suggesting that it may play a role in additional neuron-specific activities. UCHL1 has both ubiquitin E3 ligase and hydrolase activities (Liu et al., 2002). Besides hydrolyzing Ub from a poly-Ub chain for recycling, UCHL1 also ligates Ub onto specific proteins, tagging these proteins for transport for proteasomal
Conclusions
UPP function is impaired in the aging brain. Neurodegenerative diseases are associated with the accumulation of toxic proteins, which may be in part due to dysfunction of the UPP. Cerebral ischemia results in UPP dysfunction and may contribute to UPP dysfunction found in the aging brain and in neurodegenerative diseases. Modification of UCHL1 by reactive lipids produced after cerebral ischemia may be an important mechanism by which the UPP is disrupted in the aging brain. Preventing
Disclosure/Conflict of interest
The authors declare no conflict of interest. The contents do not represent the views of the Department of Veterans Affairs or the United States Government.
Acknowledgements
This work was supported by the National Institutes of Health NINDS R01NS37549, 2015 (SHG). The authors thank Marie Rose for figure preparation and editorial assistance.
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