TFEB overexpression prevents neurodegeneration in experimental synucleinopathies


Arotcarena ML, Bourdenx M, Dutheil N, Thiolat ML, Doudnikoff E, Dovero S, Ballabio A, Fernagut PO, Meissner WG, Bezard E, Dehay B.

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Synucleinopathies are neurodegenerative diseases characterized by the cellular accumulation of a protein called α-synuclein, in its misfolded conformation, into the central nervous system. Parkinson’s disease is the most common synucleinopathy, characterized by a neuronal α-synuclein accumulation while Multiple System Atrophy, the second most prevalent synucleinopathy, is characterized by the accumulation of the protein in the oligodendrocytes, the neuronal protective cells. Misfolded α-synuclein cellular accumulation plays a major pathological role in neuronal cell loss. In this article, we adopted a strategy aiming to increase α-synuclein clearance via the activation of the protein degradation machinery – called autophagy – in the affected cells using rodent models of Parkinson’s disease and Multiple System Atrophy. We showed that targeting the neuronal cells for Parkinson’s disease or the oligodendrocytes for Multiple System Atrophy cases is an efficient strategy to induce neuroprotection. Thus, we demonstrated for the first time that targeting α-synuclein degradation in a cell-specific way according to the synucleinopathy, is a promising therapeutic strategy for these neurodegenerative diseases.

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