Role of ubiquitin-mediated proteolysis in the pathogenesis of neurodegenerative disorders |
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Authors: | Layfield Robert Cavey James R Lowe James |
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Affiliation: | School of Biomedical Sciences, University of Nottingham Medical School, Queen's Medical Centre, Nottingham NG7 2UH, UK. robert.layfield@nottingham.ac.uk |
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Abstract: | Intraneuronal inclusions containing ubiquitylated filamentous protein aggregates are a common feature of many of the major human neurodegenerative disorders, including Alzheimer's and Parkinson's disease. Loss of function mutations in enzymes of the ubiquitin conjugation/deconjugation pathway are sufficient to cause familial forms of neurodegenerative diseases, suggesting that failure of ubiquitin-mediated proteolysis could also be central to inclusion formation in the more common sporadic cases. Examination of ubiquitin-positive inclusions at the protein level provides evidence of attempted proteasomal proteolysis, however close inspection of the temporal aspects of inclusion formation indicates that ubiquitylation is probably a late event. In this regard, the presence of ubiquitin within inclusions of idiopathic neurodegenerative disorders may indicate not a primary dysfunction of ubiquitin-mediated proteolysis, but rather a secondary, presumably protective cellular response. Within this model, other factors are likely to be initiating in inclusion biogenesis. Consistent with these proposals, non-ubiquitylated forms of the principal ubiquitylated components of Alzheimer's disease neurofibrillary tangles and Parkinson's disease Lewy bodies, tau and alpha-synuclein proteins, respectively, can be degraded by proteasomes in a pathway which does not have an absolute requirement for ubiquitylation. Inhibition of proteasome function in the pathological state, as has been reported in both Alzheimer's and Parkinson's disease, could therefore contribute both to accumulation of non-ubiquitylated forms of aggregation-prone neuronal proteins, as well as impaired clearance of ubiquitylated aggregates. |
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Keywords: | E1, ubiquitin-activating enzyme E2, ubiquitin-conjugating enzyme E3, ubiquitin-ligase enzyme AD, Alzheimer’s disease DLB, dementia with Lewy bodies NFT, neurofibrillary tangle Aβ, amyloid beta FTDP-17, frontotemporal dementia with Parkinsonism linked to chromosome 17 LB, Lewy body PD, Parkinson’s disease |
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