Elsevier

Ageing Research Reviews

Volume 34, March 2017, Pages 30-38
Ageing Research Reviews

Review
Life and death in the trash heap: The ubiquitin proteasome pathway and UCHL1 in brain aging, neurodegenerative disease and cerebral Ischemia

https://doi.org/10.1016/j.arr.2016.09.011Get rights and content

Highlights

  • The UPP is essential for removing abnormal proteins from the neuron.

  • UPP dysfunction occurs in normal aging and neurodegenerative diseases.

  • UPP disruption by ischemia may contribute to the risk of neurodegenerative diseases.

  • UCHL1 is inhibited after ischemia resulting in UPP dysfunction.

  • Restoring UCHL1 activity is a novel therapeutic approach for these disorders.

Abstract

The ubiquitin proteasome pathway (UPP) is essential for removing abnormal proteins and preventing accumulation of potentially toxic proteins within the neuron. UPP dysfunction occurs with normal aging and is associated with abnormal accumulation of protein aggregates within neurons in neurodegenerative diseases. Ischemia disrupts UPP function and thus may contribute to UPP dysfunction seen in the aging brain and in neurodegenerative diseases. Ubiquitin carboxy-terminal hydrolase L1 (UCHL1), an important component of the UPP in the neuron, is covalently modified and its activity inhibited by reactive lipids produced after ischemia. As a result, degradation of toxic proteins is impaired which may exacerbate neuronal function and cell death in stroke and neurodegenerative diseases. Preserving or restoring UCHL1 activity may be an effective therapeutic strategy in stroke and neurodegenerative diseases.

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.

References (149)

  • A. Gupta et al.

    Impaired abeta clearance: a potential link between atherosclerosis and Alzheimer’s disease

    Front. Aging Neurosci.

    (2015)
  • M. Hasegawa et al.

    Phosphorylated alpha-synuclein is ubiquitinated in alpha-synucleinopathy lesions

    J. Biol. Chem.

    (2002)
  • M.D. Hill et al.

    Safety and efficacy of NA-1 in patients with iatrogenic stroke after endovascular aneurysm repair (ENACT): a phase 2, randomised, double-blind, placebo-controlled trial

    Lancet Neurol.

    (2012)
  • T.J. Hohman et al.

    Stroke risk interacts with Alzheimer’s disease biomarkers on brain aging outcomes

    Neurobiol. Aging

    (2015)
  • N.M. Hooper

    Could inhibition of the proteasome cause mad cow disease?

    Trends Biotechnol.

    (2003)
  • Y. Imai et al.

    An unfolded putative transmembrane polypeptide, which can lead to endoplasmic reticulum stress, is a substrate of Parkin

    Cell

    (2001)
  • T. Kabuta et al.

    Aberrant interaction between Parkinson disease-associated mutant UCH-L1 and the lysosomal receptor for chaperone-mediated autophagy

    J. Biol. Chem.

    (2008)
  • M.A. Kalchman et al.

    Huntingtin is ubiquitinated and interacts with a specific ubiquitin-conjugating enzyme

    J. Biol. Chem.

    (1996)
  • A. Kapasi et al.

    Vascular contributions to cognitive impairment, clinical Alzheimer’s disease, and dementia in older persons

    Biochim. Biophys. Acta

    (2016)
  • J.N. Keller et al.

    Decreased levels of proteasome activity and proteasome expression in aging spinal cord

    Neuroscience

    (2000)
  • M.A. Koike et al.

    Oligemic hypoperfusion differentially affects tau and amyloid-{beta}

    Am. J. Pathol.

    (2010)
  • Z. Li et al.

    Delta12-prostaglandin J2 inhibits the ubiquitin hydrolase UCH-L1 and elicits ubiquitin-protein aggregation without proteasome inhibition

    Biochem. Biophys. Res. Commun.

    (2004)
  • Y. Liu et al.

    The UCH-L1 gene encodes two opposing enzymatic activities that affect alpha-synuclein degradation and Parkinson’s disease susceptibility

    Cell

    (2002)
  • H. Liu et al.

    Modification of ubiquitin-C-terminal hydrolase-L1 by cyclopentenone prostaglandins exacerbates hypoxic injury

    Neurobiol. Dis.

    (2011)
  • H. Liu et al.

    Prostaglandin D2 toxicity in primary neurons is mediated through its bioactive cyclopentenone metabolites

    Neurotoxicology

    (2013)
  • H. Liu et al.

    COX2-derived primary and cyclopentenone prostaglandins are increased after asphyxial cardiac arrest

    Brain Res.

    (2013)
  • M. Ahmad et al.

    Inflammation in ischemic stroke: mechanisms, consequences and possible drug targets

    CNS Neurol. Disord. Drug Targets

    (2014)
  • A. Asai et al.

    Selective proteasomal dysfunction in the hippocampal CA1 region after transient forebrain ischemia

    J. Cereb. Blood Flow Metab.

    (2002)
  • J. Avila et al.

    Tau and neuron aging

    Aging Dis.

    (2013)
  • E.M. Balfors et al.

    Impairment of cerebral perfusion during obstructive sleep apneas

    Am. J. Respir. Crit. Care Med.

    (1994)
  • K. Bilguvar et al.

    Recessive loss of function of the neuronal ubiquitin hydrolase UCHL1 leads to early-onset progressive neurodegeneration

    Proc. Natl. Acad. Sci. U. S. A.

    (2013)
  • B.C. Braun et al.

    The base of the proteasome regulatory particle exhibits chaperone-like activity

    Nat. Cell Biol.

    (1999)
  • A.E. Cartier et al.

    Regulation of synaptic structure by ubiquitin C-terminal hydrolase L1

    J. Neurosci.

    (2009)
  • Y. Chai et al.

    Evidence for proteasome involvement in polyglutamine disease: localization to nuclear inclusions in SCA3/MJD and suppression of polyglutamine aggregation in vitro

    Hum. Mol. Genet.

    (1999)
  • F. Chen et al.

    Ubiquitin carboxyl-terminal hydrolase L1 is required for maintaining the structure and function of the neuromuscular junction

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • H. Chen et al.

    Oxidative stress in ischemic brain damage: mechanisms of cell death and potential molecular targets for neuroprotection

    Antioxid. Redox Signal.

    (2011)
  • P.C. Chen et al.

    Ubiquitin homeostasis is critical for synaptic development and function

    J. Neurosci.

    (2011)
  • K.K. Chung et al.

    Nitric oxide, S-nitrosylation and neurodegeneration

    Cell. Mol. Biol. (Noisy-le-grand)

    (2005)
  • K.K. Chung

    Modulation of pro-survival proteins by S-nitrosylation: implications for neurodegeneration

    Apoptosis

    (2010)
  • A. Ciechanover et al.

    Degradation of misfolded proteins in neurodegenerative diseases: therapeutic targets and strategies

    Exp. Mol. Med.

    (2015)
  • D.W. Cleveland et al.

    Oxidation versus aggregation—how do SOD1 mutants cause ALS?

    Nat. Med.

    (2000)
  • K.J. Davies et al.

    Preferential degradation of oxidized proteins by the 20S proteasome may be inhibited in aging and in inflammatory neuromuscular diseases

    Neurology

    (2006)
  • J.M. Deger et al.

    The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration

    Aging Cell

    (2015)
  • P. Deriziotis et al.

    Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry

    EMBO J.

    (2011)
  • S. Engelender

    Ubiquitination of alpha-synuclein and autophagy in Parkinson’s disease

    Autophagy

    (2008)
  • Z. Erpapazoglou et al.

    Versatile roles of k63-linked ubiquitin chains in trafficking

    Cells

    (2014)
  • M.E. Figueiredo-Pereira et al.

    Neuroinflammation and J2 prostaglandins: linking impairment of the ubiquitin-proteasome pathway and mitochondria to neurodegeneration

    Front. Mol. Neurosci.

    (2014)
  • D. Finley

    Recognition and processing of ubiquitin-protein conjugates by the proteasome

    Annu. Rev. Biochem.

    (2009)
  • H.R. Fuller et al.

    Spinal muscular atrophy patient iPSC-derived motor neurons have reduced expression of proteins important in neuronal development

    Front. Cell. Neurosci.

    (2015)
  • K. Gadhave et al.

    The ubiquitin proteasomal system: a potential target for the management of Alzheimer’s disease

    J. Cell. Mol. Med.

    (2016)
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