Skip to main content

The Role of Phosphorylation in Synucleinopathies: Focus on Parkinson's Disease

Buy Article:

$63.00 plus tax (Refund Policy)

Abstract:

α-Synuclein is a soluble, natively unfolded protein that is highly enriched in the presynaptic terminals of neurons in the central nervous system. Interest in α-synuclein has increased markedly following the discovery of a relationship between its dysfunction and several neurodegenerative diseases, including Parkinson's disease. The physiological functions of α-synuclein remain to be fully defined, although recent data suggest a role in regulating membrane stability and neuronal plasticity. In addition, there is increasing evidence pointing to phosphorylation as playing an important role in the oligomerization, fibrillogenesis, Lewy body formation, and neurotoxicity of α-synuclein in Parkinson's disease. Immunohistochemical and biochemical studies reveal that the majority of α-synuclein within inclusions from patients with Parkinson's disease and other synucleinopathies is phosphorylated at Ser129. α-Synuclein can be phosphorylated in vitro also at Ser87, and three C-terminal tyrosine residues (Tyr125, Tyr 133, and Tyr136). Tyrosine 125 phosphorylation diminishes during the normal aging process in both humans and flies. Notably, cortical tissue from patients with Parkinson's disease-related synucleinopathy dementia with Lewy bodies showed less phosphorylation at Tyr125. While phosphorylation at Ser87 is enhanced in synucleinopathies, it inhibits α-synuclein oligomerization, and influences synuclein-membrane interactions. The possibility that α-synuclein neurotoxicity in Parkinson's disease and related synucleinopathies may result from an imbalance between the detrimental, oligomer-promoting effect of Ser129 phosphorylation and a neuroprotective action of Ser87/Tyr125 phosphorylation that inhibits toxic oligomer formation merits consideration, as will be discussed in this article.





Keywords: Parkinson's disease; aggregation; neurotoxicity; phosphorylation; synucleinopathies; transgenic; α-synuclein

Document Type: Research Article

DOI: http://dx.doi.org/10.2174/187152710791556140

Affiliations: Department of Veterinary Science, University of Padova (CRIBI), Via G. Colombo, 3, 35121 Padova, Italy.

Publication date: August 1, 2010

More about this publication?
  • CNS & Neurological Disorders - Drug Targets aims to cover all the latest and outstanding developments on the medicinal chemistry, pharmacology, molecular biology, genomics and biochemistry of contemporary molecular targets involved in neurological and central nervous system (CNS) disorders e.g. disease specific proteins, receptors, enzymes, genes. Each issue of the journal will contain a series of timely in-depth reviews written by leaders in the field covering a range of current topics on drug targets involved in neurological and CNS disorders. As the discovery, identification, characterization and validation of novel human drug targets for neurological and CNS drug discovery continues to grow; this journal will be essential reading for all pharmaceutical scientists involved in drug discovery and development.
ben/cnsnddt/2010/00000009/00000004/art00009
dcterms_title,dcterms_description,pub_keyword
6
5
20
40
5

Access Key

Free Content
Free content
New Content
New content
Open Access Content
Open access content
Subscribed Content
Subscribed content
Free Trial Content
Free trial content
Cookie Policy
X
Cookie Policy
ingentaconnect website makes use of cookies so as to keep track of data that you have filled in. I am Happy with this Find out more