. A pathologic cascade leading to synaptic dysfunction in alpha-synuclein-induced neurodegeneration. J Neurosci. 2010 Jun 16;30(24):8083-95. PubMed.

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  1. This elegant study by Scott et al. takes advantage of primary neuron cultures from α-synuclein-GFP-transgenic mice to examine the effects of modest α-synuclein overexpression on presynaptic proteins. They find convincing evidence that α-synuclein can diminish levels of several critical presynaptic proteins involved in exocytosis and endocytosis. The authors also detect significant reductions in miniEPSC frequency, diminished presynaptic exocytosis, and altered vesicle size by EM in α-synuclein-overexpressing neurons. Thus, physiologically relevant increases in α-synuclein produce robust functional consequences that closely mimic those observed in animal models of endocytic protein deficiency.

    The authors point out that similar effects on presynaptic proteins have recently been shown following Aβ oligomer exposure (Parodi et al., 2010), suggesting a possible common mechanism of synaptic dysfunction between AD and synucleinopathies. It is intriguing to speculate that this potential shared mechanism of synaptic dysfunction may play a role in the acceleration of cognitive decline and aggressive disease course in patients and transgenic mice that co-exhibit both AD and Lewy body pathologies (Olchney et al., 1998; Clinton et al., 2010).

    References:

    . Beta-amyloid causes depletion of synaptic vesicles leading to neurotransmission failure. J Biol Chem. 2010 Jan 22;285(4):2506-14. PubMed.

    . Cognitive decline is faster in Lewy body variant than in Alzheimer's disease. Neurology. 1998 Aug;51(2):351-7. PubMed.

    . Synergistic Interactions between Abeta, tau, and alpha-synuclein: acceleration of neuropathology and cognitive decline. J Neurosci. 2010 May 26;30(21):7281-9. PubMed.

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