No coin nor oath required. For personal study only.
Objective: To illustrate the relevance of โฃ-synuclein for a molecular understanding of Lewy body diseases and multiple system atrophy.
Background: Parkinson's disease is the most common movement disorder and the second most common neurodegenerative disease. Neuropathologically, it is characterized by the degeneration of populations of nerve cells that develop filamentous inclusions in the form of Lewy bodies and Lewy neurites. Similar inclusions are also characteristic of dementia with Lewy bodies and several other neurodegenerative diseases. For a long time, the biochemical composition of the Lewy body filaments and their relevance for the neurodegenerative process remained unknown.
Results: In 1997, a missense mutation in the โฃ-synuclein gene was identified in a family with a rare inherited form of Parkinson's disease (the Contursi kindred). In the same year, Lewy bodies and Lewy neurites from cases of sporadic Parkinson's disease and dementia with Lewy bodies were shown to be strongly immunoreactive for โฃ-synuclein. These findings brought the little studied โฃ-synuclein to centre stage. It is now well established that โฃ-synuclein is the major component of the abnormal filaments that characteristize Lewy bodies and Lewy neurites. The filamentous inclusions of multiple system atrophy were also found to be made of โฃ-synuclein, thus providing an unexpected molecular link with Lewy body diseases. Recombinant โฃ-synuclein assembles into filaments with similar morphologies to those found in the human diseases and with a cross-beta fibre diffraction pattern characteristic of amyloid. The related proteins โค-synuclein and โฅ-synuclein are poor at assembling into filaments. They are not present in the pathological filamentous lesions and have not been found to be linked to genetic disease. Beta-synuclein and โฅ-synuclein have been shown to inhibit the self-assembly of โฃ-synuclein.
Conclusion: The work done over the past five years has established the โฃ-synucleinopathies as a major class of neurodegenerative disease.
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