Synphilin-1 isoforms in Parkinson's disease: regulation by phosphorylation and ubiquitylation

Cell. Mol. Life Sci. 65 (2008) 80 88 1420-682X/08/010080-9DOI 10.1007/s00018-007-7343-0 Birkh user Verlag, Basel, 2007

Cellular and Molecular Life Sciences

Visions & Reflections (Minireview)

Synphilin-1 isoforms in Parkinson s disease: regulation by

phosphorylation and ubiquitylation

R. Szargel, R. Rott and S. Engelender*

Department of Pharmacology, The B. Rappaport Institute of Medical Research, Technion-Israel Institute of Technology, Haifa 31096 (Israel), e-mail: [email protected]

Received 26 July 2007; received after revision 19 September 2007; accepted 15 October 2007 Online First 5 November 2007

Abstract. Parkinson s disease (PD) is characterized by the death of dopaminergic neurons and the presence of Lewy bodies in the substantia nigra pars compacta.The mechanisms involved in the death of neurons as well as the role of Lewy bodies in the pathogenesis of the disease are still unclear. Lewy bodies are made of aggregated proteins, in which a-synuclein represents their major component. a-Synuclein interacts with synphilin-1, a protein that is also present in Lewy bodies. When expressed in cells, synphilin-1 forms inclusions together with a-synuclein that resemble Lewy bodies. Synphilin-1 is ubiquitylated by various

E3 ubiquitin-ligases, such as SIAH, parkin and dorfin.

Ubiquitylation of synphilin-1 by SIAH is essential for its aggregation into inclusions. We recently identified a new synphilin-1 isoform, synphilin-1A, that is toxic to neurons, aggregation-prone and accumulates in detergent-insoluble fractions of brains from a-synucleinopathy patients. Synphilin-1A inclusions recruit both a-synuclein and synphilin-1. Aggregation of synphilin-1 and synphilin-1A seems to be protective to cells. We now discuss several aspects of the neuro-biology and pathology of synphilin-1 isoforms, focusing on possible implications for PD.

Keywords. Parkinson s disease, synphilin, a-synuclein, ubiquitylation, inclusion body, Lewy body.

Synphilin-1 isoforms: interaction with several Parkinson s disease proteins

In the last decade, different gene mutations have been shown to cause familial Parkinson s disease (PD) [1]. a-Synuclein was the first gene found to be mutated in families with PD [25]. Although mutations in the asynuclein gene represent a rare cause of PD [1], its robust presence in Lewy bodies [6] and ability to form fibrils [7] place a-synuclein as a major player in the pathogenesis of sporadic PD. Despite the central role of a-synuclein in the disease, the mechanisms by which a-synuclein promotes neurodegeneration and how its

aggregation into Lewy bodies takes part in this process...