Alpha-Synuclein Oligomers as a Biomarker Candidate for Parkinson's Disease and Disorders

Abstract

Developing effective treatments for neurodegenerative diseases is one of the greatest medical challenges of the 21st century. Parkinson's disease (PD) and dementia with Lewy bodies (DLB) are very common neurological disorders of the elderly (Jankovic et al., 2008). Although many of these clinical entities have been recognized for more than a hundred years, it is only during the past fifteen years that the molecular events that precipitate the diseases have begun to be understood. Mutations in the α-synuclein gene cause early-onset PD, often associated with dementia, and one an α-synuclein mutation segregated with pure DLB (with no Alzheimer's pathology). Neuropathologically these diseases are characterized by the presence of Lewy bodies, intraneuronal inclusions mostly composed of α-synuclein protein fibrils, cementing the notion that this protein has a central role in Lewy body diseases (LBD). Despite the progress that has been made in understanding the underlying disease mechanisms of LBD, there remains an urgent need to develop methods for use in diagnosis. The development of reliable surrogate markers for the presence and abundance of α-synuclein lesions (Lewy bodies) in the brain would naturally facilitate a more streamlined work-up during the early care of PD and DLB patients, and importantly, allow for the biologically guided evaluation of future drug trials aimed at neuroprotection in the synucleinopathies. Recently, we generated new antibodies specific for different forms of α-synuclein such as oligomeric-α-synuclein (o-α-synuclein), phosphorylated-α-synuclein at serine 129 (p-S129-α-synuclein) or total-α-synuclein (t-α-synuclein), to develop highly specific and sensitive ELISA systems to assess the levels of these species in biological fluids. Next, we utilized our assays to explore the potential use of α-synuclein species as biomarkers for PD in cerebrospinal fluid (CSF) samples from a cross-sectional cohort of 46 PD patients and 48 age-matched healthy controls. Thereafter, we validated our results in large longitudinal DATATOP cohort (n = 242) over two-year follow-up period). In our study we also investigated the potential predictive role of CSF Alzheimer's disease (AD) core biomarkers (Aβ42, total tau, p-tau). In our study we also investigated the added predictive value of CSF AD core biomarkers (Aβ42, total tau, p-tau) to CSF α-synuclein species. Interestingly, a strong positive correlation between the changes in CSF t- and o-α-synuclein levels was noted. Such a strong correlation clearly suggests that the increase of CSF t-α-synuclein levels at the early stages of the disease lead to the formation and accumulation of the pathogenic species of o-α-synuclein in the brain that cause neuronal cell death. It has been shown that soluble o-α-synuclein are elevated in brain homogenates from PD and DLB compared to normal brains (Sharon, et al., 2003; Paleologou, et al., 2009). Together with the results from our previous studies, we provide strong evidence for the important role of o-α-synuclein in the pathogenesis of PD and other synucleinopathies (El-Agnaf et al., 2003). Consistent with our recent study (Parnetti, et al., 2014), we also found that the change in CSF Aβ42 levels correlated with the change in UPDRS-mental scores, suggesting that CSF Aβ42 may aid in predicting cognitive decline in PD patients. It's worth mentioning that one of the many important features that distinguished the DATATOP study from other studies is that the untreated PD subjects enrolled in the DATATOP study were at a very early stage of the disease; a stage estimated to be earlier than most of the other clinical trials. At baseline, PD patients presented with minimal disability and were followed until just prior to the initiation of the dopamine replacement therapy, and this is reflected in the low HY2:461–462. Jankovic, J. Parkinson's disease: clinical features and diagnosis. J Neurol Neurosurg Psychiatry 2008;79:368–376, doi:10.1136/jnnp.2007.131045. Kordower, J. H. et al. Disease duration and the integrity of the nigrostriatal system in Parkinson's disease. Brain 2013;136:2419–2431, doi:10.1093/brain/awt192. Paleologou, K. E. et al. Detection of elevated levels of soluble alpha-synuclein oligomers in post-mortem brain extracts from patients with dementia with Lewy bodies. Brain 2009;132, doi:10.1093/brain/awn349. Parnetti, L. et al. Differential role of CSF alpha-synuclein species, tau, and Aβ42 in Parkinson's Disease. Front Aging Neurosci 2014;6:53, doi:10.3389/fnagi.2014.00053. Sharon, R. et al. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson's disease. Neuron 2003;37:583–595. Toledo, J. B., Korff, A., Shaw, L. M., Trojanowski, J. Q. & Zhang, J. CSF α-synuclein improves diagnostic and prognostic performance of CSF tau and Aβ in Alzheimer's disease. Acta Neuropathol 2013;126:683–697, doi:10.1007/s00401-013-1148-z.