• Energy Research

TorsinA, a novel protein in which a mutation causes dominant, early onset torsion dystonia, may serve as a chaperone for misfolded proteins that require refolding or degradation. It has been hypothesized that misfolded alpha-synuclein, a protein in which two mutations cause autosomal dominantly inherited Parkinson's disease, serves as a nidus for the development of a Lewy body. We hypothesized that torsinA plays a role in the cellular processing of alpha-synuclein. We demonstrate that anti-torsin antibodies stain Lewy bodies and Lewy neurites in the substantia nigra and cortex. Using sensitive fluorescent resonance energy transfer (FRET) techniques, we find evidence of a close association between torsinA and alpha-synuclein in Lewy bodies.

α‐Synuclein is a major component of Lewy bodies, a neuropathological feature of Parkinson's disease. Two α‐synuclein mutations, Ala53Thr and Ala30Pro, are associated with early onset, familial forms of the disease. Recently, synphilin‐1, a protein found to interact with α‐synuclein by yeast two hybrid techniques, was detected in Lewy bodies. In this study we report the interaction of α‐synuclein and synphilin‐1 in human neuroglioma cells using a sensitive fluorescence resonance energy transfer technique. We demonstrate that the C‐terminus of α‐synuclein is closely associated with the C‐terminus of synphilin‐1. A weak interaction occurs between the N‐terminus of α‐synuclein and synphilin‐1. The familial Parkinson's disease associated mutations of α‐synuclein (Ala53Thr and Ala30Pro) also demonstrate a strong interaction between their C‐terminal regions and synphilin‐1. However, compared with wild‐type α‐synuclein, significantly less energy transfer occurs between the C‐terminus of Ala53Thr α‐synuclein and synphilin‐1, suggesting that the Ala53Thr mutation alters the conformation of α‐synuclein in relation to synphilin‐1.