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Tokuda T, Qureshi MM, Ardah MT, Varghese S, Shehab SA, Kasai T, Ishigami N, Tamaoka A, Nakagawa M, El-Agnaf OM. Detection of elevated levels of α-synuclein oligomers in CSF from patients with Parkinson disease. Neurology. 2010 Nov 16;75(20):1766-72. PubMed.
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Uppsala University
The potential of CSF α-synuclein as a biomarker for Parkinson’s disease has been investigated by Tokuda et al. The authors confirm their own previously reported findings of decreased total CSF α-synuclein in patients as compared to controls. What is novel and intriguing with the current report is the finding of increased levels of oligomeric α-synuclein in CSF from Parkinson’s patients. Furthermore, an increased oligomer/total α-synuclein ratio offers an even better disease biomarker with sensitivity and specificity of approximately 90 percent. Importantly, the authors also state that the increased ratio is even more pronounced among cases at a milder disease stage.
These findings indicate striking similarities between α-synuclein and Aβ as CSF biomarkers for Parkinson’s disease and Alzheimer’s disease, respectively. Decreased CSF Aβ42, together with increased tau, has for a long time been the most robust biomarker for Alzheimer’s disease. Moreover, Fukumoto and colleagues recently showed that oligomeric Aβ is increased in CSF from Alzheimer’s patients (1).
Among several possible explanations, the combination of lowered total protein and increased oligomeric protein may be explained by the fact that monomeric α-synuclein and Aβ both are consumed as a result of fibril formation. Meanwhile, at least parts of the more toxic oligomeric forms may be off-pathway and thus remain in increased amounts throughout the CNS in the respective disorders.
The assays developed by Tokuda et al. and Fukumoto et al. probably detect a vast range of multimeric proteins, ranging from dimers to large oligomers or protofibrils. The levels of oligomeric α-synuclein were only given as arbitrary units, as it was difficult to generate a reliable standard curve for such protein species. Nevertheless, these findings are very interesting and promising, but need to be replicated by other research teams. In addition, future novel assays might be developed in order to discriminate which oligomeric species are most appropriate as disease biomarkers. Preferably, such assays could utilize antibodies selective for various oligomers of α-synuclein and Aβ, respectively.
References:
Fukumoto H, Tokuda T, Kasai T, Ishigami N, Hidaka H, Kondo M, Allsop D, Nakagawa M. High-molecular-weight beta-amyloid oligomers are elevated in cerebrospinal fluid of Alzheimer patients. FASEB J. 2010 Aug;24(8):2716-26. PubMed.
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