Scott D, Roy S.
α-Synuclein inhibits intersynaptic vesicle mobility and maintains recycling-pool homeostasis.
J Neurosci. 2012 Jul 25;32(30):10129-35.
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Several recent studies have reported significantly decreased levels of cerebrospinal fluid (CSF) α-synuclein levels specifically in patients with synucleinopathies including Parkinson's disease (PD), multiple systems atrophy (MSA), and dementia with Lewy bodies (DLB), suggesting CSF α-synuclein levels as a biomarker for α-synucleinopathy.
Interestingly, Tateno and colleagues (Tateno et al., 2011) reported significantly increased CSF levels of α-synuclein in AD patients, and further proposed CSF α-synuclein as a potent biomarker to aid clinical differentiation between AD and α-synucleinopathies. Also, we recently reported highly significant and strong correlations between CSF levels of tau, considered to be a marker of neurodegeneration, and CSF α-synuclein in patients with AD, DLB, and PD (Wennström et al., 2012); however, the biological significance of this association is not yet clear. Therefore, it is interesting to note that Saman and colleagues (Saman et al., 2011) recently showed that tau can be secreted through an exosome-mediated mechanism, similar to α-synuclein, and which, according to Emmanouilidou and colleagues, can be found in human CSF as phosphorylated at Thr181 (Emmanouilidou et al., 2010). In regard to this background, the recent findings by Larson et al. provide more detailed evidence of links between α-synuclein and AD pathology.
In a sophisticated, well-executed translational research study, they suggest an interesting novel link between α-synuclein and human AD pathophysiology—intracellular soluble protein and α-synuclein transcripts were 2.31- and 1.67-fold, respectively, increased in AD brains versus control brains. More importantly, the accumulation of α-synuclein appeared independent of Lewy body pathology. These findings support previous CSF data indicating altered levels of α-synuclein in patients with AD.
The results of Larson et al. also highlight a significant association between increased α-synuclein levels and memory deficits, possibly mediated by a reduction in expression of synaptic vesicular proteins, in transgenic mice overexpressing human α-synuclein.
Thus, the authors suggest that development of cognitive symptoms in AD may be promoted by soluble α-synuclein monomers. Most intriguing are their findings suggesting that a synergism between Aβ/APP and human tau, as tested in transgenic mouse models, is needed in order to upregulate the expression levels of α-synuclein. The authors suggest a model in which interactions between soluble Aβ and tau lead to accumulation of soluble α-synuclein, which in turn leads to alterations of presynaptic vesicle protein expression and impaired neurotransmitter release. These novel findings position α-synuclein as a key player in AD pathophysiology, in the absence of Lewy pathology, and may carry implications for future drug discovery trials for disease-modifying agents as well as for the use of biomarkers for early detection and monitoring of AD disease progression.