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Protease Activity in the Aging Brain

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Abstract:

There is abundant evidence for the accumulation of damaged and misfolded proteins in the aging mammalian brain. This accumulation may result from an increasing burden of oxidative damage combined with a diminished capacity to degrade aberrant proteins through the lysosomal and proteasomal pathways (the two major systems for the regulated disassembly of proteins). A chronic proteolytic deficit in either or both systems is predicted to lead to a neurotoxic crisis that has been described as “garbage catastrophe.” The evidence for the decline in proteolytic capacity of the degradative systems and the hypothesized events leading up to their catastrophic failure are reviewed.

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Abbreviations

Atg:

autophagy related gene

ATPase:

enzyme catalyzing cleavage of adenosine triphosphate

ax:

ataxia

CA:

Cornu Ammonis (Ammon's horn), a region of the hippocampus

CLN:

ceroid lipofuscinosis, neuronal

CNS:

central nervous system

DG:

dentate gyrus, a region of the hippocampus

ERAD:

endoplasmic reticulum associated degradation system

H:

Hilus, a region of the hippocampus

Hsc:

cytosolic heat shock protein

KFERQ:

motif targeting proteins to the lysosome (refers to single letter amino acid code)

NCL:

neuronal ceroid lipofuscinosis

PPT:

palmitoyl protein thioesterase

ROS:

reactive oxygen species

UCH:

ubiquitin carboxyterminal hydrolase

UPS:

ubiquitin proteasome system

Usp:

ubiquitin specific protease

19S:

cap structure of the proteasome (19S refers to centrifugal sedimentation value)

20S:

catalytic core of the proteasome (20S refers to centrifugal sedimentation value)

26S:

complete proteasome assembly with core rings and end caps (26S refers to centrifugal sedimentation value)

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Acknowledgments

The author is grateful to Dr. John Woulfe for the image appearing in Figure 23-1 , and to Mei Zhang for the immunohistochemical staining in Figure 23-2 . Mechanisms proposed in the chapter have been refined through serial discussions with Maria Tsirigotis, to whom the author is indebted. The author's work is supported by the Institute of Aging, Canadian Institutes of Health Research.

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  1. D. A. Gray
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Editors and Affiliations

  1. Center for Neurochemistry, Nathan S. Kline Institute for Psychiatric Research, 140 Old Orangeburg Road, Orangeburg, Newyork, 10962, USA

    Abel Lajtha (Director) (Director)

  2. Department of Neurosciences Division of Neurology, Medical University of South Carolina, 96 Jonathan Lucas Street Suite 309, Charleston, SC 29425, USA

    Naren Banik (Professor) (Professor)

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Gray, D.A. (2007). Protease Activity in the Aging Brain. In: Lajtha, A., Banik, N. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-30379-6_23

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