Abstract

Neurodegenerative diseases such as Parkinson, Alzheimer’s, and Huntington are proteopathic disorders characterized by the accumulation of intracellular insoluble aggregates of misfolded proteins and are one of the major medical concerns of our modern society. Particularly, Parkinson disease is a synucleinopathy caused by the cytosolic aggregation of α-Synuclein into Lewy bodies (1). Although its biological function remains obscure, numerous lines of evidence clearly point at α-Synuclein oligomers or aggregates as the causative agent of Parkinson disease (1). However, despite intense research, the detailed etiology of Parkinson disease remains elusive. Apart from missense point mutations in the α-Synuclein gene (which account for familial cases of early onset Parkinson disease), increased intracellular expression levels and posttranslational modifications of α-Synuclein have been implicated in the formation of Lewy bodies. Currently, known modifications of α-Synuclein include proteolytic truncation, oxidation, nitration, phosphorylation, and ubiquitination (1). The key to understanding proteopathic diseases such as Parkinson disease rests on elucidating the role of these modifications and how they influence the properties of the nascent α-Synuclein polypeptide. In their current research article, Haj-Yahya et al. report on an important milestone in the synthesis of selectively di- and tetra-ubiquitinated (K48) α-Synuclein, which can be used to study the biophysical and biochemical consequences of α-Synuclein ubiquitination (2). In addition to offering valuable insights into molecular biology of synucleinopathies, their findings also open up new horizons in the research on ubiquitination—a crucial posttranslational protein modification involved in quintessential aspects of cell biology (3). Ubiquitin is a small protein of 76 amino acids and is highly conserved among all eukaryotic organisms. Ubiquitin … [↵][1]1To whom correspondence should be addressed. Email: dikic{at}biochem2.uni-frankfurt.de. [1]: #xref-corresp-1-1

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