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A Focus on the Beneficial Effects of Alpha Synuclein and a Re-Appraisal of Synucleinopathies

[ Vol. 19 , Issue. 6 ]

Author(s):

Larisa Ryskalin, Carla L. Busceti, Fiona Limanaqi, Francesca Biagioni, Stefano Gambardella and Francesco Fornai*   Pages 598 - 611 ( 14 )

Abstract:


Alpha synuclein (α-syn) belongs to a class of proteins which are commonly considered to play a detrimental role in neuronal survival. This assumption is based on the occurrence of a severe neuronal degeneration in patients carrying a multiplication of the α-syn gene (SNCA) and in a variety of experimental models, where overexpression of α-syn leads to cell death and neurological impairment. In these conditions, a higher amount of normally structured α-syn produces a damage, which is even worse compared with that produced by α-syn owning an abnormal structure (as occurring following point gene mutations). In line with this, knocking out the expression of α-syn is reported to protect from specific neurotoxins such as 1-methyl, 4-phenyl 1,2,3,6-tetrahydropyridine (MPTP). In the present review we briefly discuss these well-known detrimental effects but we focus on findings showing that, in specific conditions α-syn is beneficial for cell survival. This occurs during methamphetamine intoxication which is counteracted by endogenous α-syn. Similarly, the dysfunction of the chaperone cysteine-string protein- alpha leads to cell pathology which is counteracted by over-expressing α-syn. In line with this, an increased expression of α-syn protects against oxidative damage produced by dopamine. Remarkably, when the lack of α-syn is combined with a depletion of β- and γ- synucleins, alterations in brain structure and function occur. This review tries to balance the evidence showing a beneficial effect with the bulk of data reporting a detrimental effect of endogenous α-syn. The specific role of α-syn as a chaperone protein is discussed to explain such a dual effect.

Keywords:

Alpha synuclein, synucleinopathies, alpha synuclein aggregates, loss-of-function, co-chaperonine, neurodegeneration, neuroprotection.

Affiliation:

Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126 Pisa, I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, Isernia, Human Anatomy, Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, via Roma 55, 56126 Pisa, I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, Isernia, I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, Isernia, I.R.C.C.S. Neuromed, Via Atinense 18, 86077 Pozzilli, Isernia

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