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Ageing Res Rev. 2017 Mar;34:30-38. doi: 10.1016/j.arr.2016.09.011. Epub 2016 Oct 1.

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

Author information

1
Geriatric Research Educational and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA. Electronic address: Steven.Graham@va.gov.
2
Geriatric Research Educational and Clinical Center, VA Pittsburgh Healthcare System, Pittsburgh, PA, USA; Department of Neurology, University of Pittsburgh, Pittsburgh, PA, USA.

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.

KEYWORDS:

Aging; Cerebral ischemia; Neurodegenerative disease; Ubiquitin; Ubiquitin carboxy-terminal hydrolase L1(UCHL1); Ubiquitin proteasome pathway (UPP)

PMID:
27702698
PMCID:
PMC5250550
DOI:
10.1016/j.arr.2016.09.011
[Indexed for MEDLINE]
Free PMC Article

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