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Ubiquitin/Proteasome and Autophagy/Lysosome Pathways: Comparison and Role in Neurodegeneration

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Handbook of Neurochemistry and Molecular Neurobiology

Abstract:

Neurodegenerative disorders, such as Alzheimer’s, Parkinson’s, and Huntington’s diseases as well as amyotrophic lateral sclerosis, are a heterogeneous group of clinical diseases that are characterized by the selective loss of neurons in specific regions of the CNS. Despite their variability they have similar features including the accumulation of misfolded proteins that eventually develop into inclusion bodies. Whether these protein deposits are pathogenic or represent a coping mechanism to prolong survival of the affected neurons is a hotly debated issue. One important point to consider is that these protein deposits are indicative of a disease-state as they are not prevalent in healthy cells. Ubiquitinated proteins are major components of these proteinaceous cytoplasmic or nuclear inclusions suggesting that impaired proteasome activity and the ubiquitination machinery may be main players in this process. Emerging data revealed that autophagosomes are also components of inclusion bodies, implicating the autophagy/lysosome pathway in neurodegenerative disorders as well. Herein, we compare some of the most important characteristics of these two pathways for intracellular protein degradation and discuss their potential role in neurodegeneration. When the proteasome is impaired, it is possible that autophagy may be the alternate pathway for clearing out aggregated ubiquitinated proteins. The question emerges if this potential “survival” mechanism can be explored as a strategy to overcome the most common feature shared by various neurodegenerative disorders, i.e., protein aggregation manifested as inclusion bodies. One potential drawback is that degradation through autophagy seems to be a “bulky,” nonspecific process. A thorough knowledge of the mechanisms involved in the targeting of substrates to autophagy will provide clues to the putative specificity of this pathway so that its ectopic manipulation will target only abnormal protein aggregates and not critical intracellular components, the removal of which may cause cell death.

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Abbreviations

AD:

Alzheimer’s disease

ALS:

amyotrophic lateral sclerosis

ALP:

autophagy/lysosome pathway

Atg:

autophagy related genes

CMA:

chaperone-mediated autophagy

E1:

ubiquitin activating enzyme

E2:

ubiquitin conjugating enzyme

E3:

ubiquitin ligase

E4:

ubiquitin-chain elongating factor

HD:

Huntington’s disease

HDAC6:

histone deacetylase 6

LC3:

microtubule-associated protein-light chain 3

LIR:

LC3-interacting region

PB1:

protein binding domain1

PD:

Parkinson’s disease

PE:

phosphatidylethanolamine

p62/SQSTM1:

p62/sequestosome1

Ub:

ubiquitin

UBA:

ubiquitin-associating domain

UBL:

ubiquitin-like

UPP:

ubiquitin/proteasome pathway

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Acknowledgments

Please note that this review is not intended to be comprehensive and we apologize to the authors whose work is not mentioned. This work was supported by NIH [NS41073 (SNRP) to M.E.F.P. (head of sub-project) from NINDS, and RR03037 to Hunter College from NIGMS/RCMI].

Authors
  1. N. Myeku
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  2. M. E. Figueiredo-Pereira
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Editor information

Editors and Affiliations

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

    Abel Lajtha (Director) (Director)

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

    Naren Banik

  3. Department of Pathology, Microbiology and Immunology, University of South Carolina School of Medicine, 29209, 6439 Garners Ferry Road Building 2, Room C11, Columbia, SC, USA

    Swapan K. Ray

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Myeku, N., Figueiredo-Pereira, M.E. (2009). Ubiquitin/Proteasome and Autophagy/Lysosome Pathways: Comparison and Role in Neurodegeneration. In: Lajtha, A., Banik, N., Ray, S.K. (eds) Handbook of Neurochemistry and Molecular Neurobiology. Springer, Boston, MA. https://doi.org/10.1007/978-0-387-30375-8_21

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