Synphilin-1: a possible molecular determinant for Parkinson's disease

SYNPHILIN-1: A POSSIBLE MOLECULAR DETERMINANT FOR PARKINSON'S DISEASE^*

SIMONE ENGELENDER AND ANA SANTORO

Departamento de Anatomia, ICB, UFRJ.

Presented by ROBERTO LENT

Parkinson's disease (PD) is one of the most common neurodegenerative diseases. The disease is characterized by a set of motor signs including, tremor, bradykinesia and rigidity. Examination of post-mortem PD brains show loss of neurons in the substantia nigra and the presence of cytoplasmic inclusions in the surviving neurons, termed Lewy bodies. PD is mostly sporadic, but some families inherit PD in an autosomal dominant manner. Mutations in the alpha-synuclein gene lead to some forms of familial PD. In addition, alpha-synuclein was found to be a major component of Lewy bodies in patients with sporadic PD, suggesting that alpha-synuclein may have an important role in the pathogenesis of PD. We recently found that alpha-synuclein interacts in vivo with a novel protein we have called synphilin-1. Synphilin-1 has no homology to any other protein in the database. It contains an ATP,GTP-binding domain and two protein-protein interaction domains, ankyrin-like repeats and coil-coiled domain. When synphilin-1 is co-transfected into mammalian cells with alpha-synuclein we observe the formation of eosinophilic inclusions resembling Lewy bodies, suggesting that synphilin-1 could modulate alpha-synuclein aggregation. We also found that, like alpha-synuclein, synphilin-1 is present in the majority of Lewy bodies of patients with PD. Synphilin-1 is present in almost 90% of Lewy bodies from substantia nigra and other regions of the brain, such as cerebral cortex, but it is absent in amyloid plaques from patients with Alzheimer's disease, suggesting that synphilin-1 could be important to the pathogenesis of PD. We have now cloned the human synphilin-1 gene, determined the organization of its 10 exons and localized it to chromosome 5q23.1-23.3. Mutation analysis of synphilin-1 may further clarify its role in the pathogenesis of genetic PD. To determine the function of synphilin-1, we are currently searching for its protein partners. Using the yeast two-hybrid system, we found that the N-terminus of synphilin-1 interacts with a protein that is still under characterization. We also found that the N-terminus of synphilin-1 is responsible for the interaction with alpha-synuclein. Proteins that specifically interact with the N-terminal portion of synphilin-1 may modulate the interaction between synphilin-1 and alpha-synuclein, and perhaps influence the formation of Lewy bodies and subsequent manifestation of the disease. Identification of additional protein partners of synphilin-1 will help understand its normal function and perhaps its role in the pathogenesis of PD. — ( June 27, 2000 ).

Publication Dates

• Publication in this collection
  05 Oct 2000
• Date of issue
  Sept 2000