Is alpha-Synuclein Pathology a Target for Treatment of Neurodegenerative Disorders?

M.      Windisch; H.   J.   Wolf; B.      Hutter-Paier; A.      Hofmeister; R.      Wronski

doi:10.2174/156720507781788783

Abstract

Alpha-synuclein is the main constituent of intra-neuronal Lewy bodies, which are characteristic of Parkinsons disease, but aggregates are also found as axonal inclusions. Alpha-synuclein pathology is found together with betaamyloid plaques and neurofibrillary tangles in Alzheimers disease and other neurodegenerative disorders. In spite of the fact that the biological function of this synaptic protein is not known so far, there is an increasing body of evidence indicating an interaction with amyloid peptides, but also with tau-hyperphosphorylation. A high proportion of alpha-synuclein purified from Lewy bodies is phosphorylated on Ser129. There are still different opinions about the toxicity of the alphasynuclein aggregates. Alpha-synuclein seems to influence different intracellular signaling pathways which are in direct relation to defense mechanisms against reactive oxygen species or apoptosis. It is obvious that overproduction of alphasynuclein, but also different mutations, are inducing the formation of aggregates. Because of the possible link to neurodegeneration, different attempts have been made to counteract alpha-synuclein aggregation. An interesting approach is utilizing beta-synuclein, a biological factor, with an aminoacid sequence closely resembling that of alpha-synuclein. Proof of concept studies indicated that overexpression of beta-synuclein is able to counteract alpha-synuclein aggregation in a transgenic animal model, while also ameliorating functional deficits. As an alternative approach, the use of low molecular beta-synuclein N-terminal peptide derivatives has been considered. Several of these structures displayed clear neuroprotective activities in tissue culture models of neurodegeneration, including beta-amyloid toxicity. Therefore it has been speculated that these compounds might have a broad therapeutic efficacy in different neurodegenerative disorders. A proof of concept study in hAPP-transgenic animals resulted in a highly significant decrease in beta-amyloid plaque load, an increase in soluble beta-amyloid peptides and a decrease in insoluble forms. There was also significant improvement of cognitive deficits in this APP transgenic mouse model following intranasal but also peripheral treatment with three of these compounds. From this study it is concluded that the observed effects of the peptides derived from beta-synuclein Nterminus are depending on both, a direct interaction with aggregation of proteins, but also with stimulation of antiapoptotic and anti-oxidative intracellular signaling pathways.

Keywords: Alpha-synuclein, Lewy bodies, Alzheimer's disease, protein aggregation, oxidative stress

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