Alterations in α-synuclein and PINK1 expression reduce neurite length and induce mitochondrial fission and Golgi fragmentation in midbrain neurons. (16th February 2020)

• Record Type: Journal Article
• Authors: Furlong, Rachel M.; O'Keeffe, Gerard W.; O'Neill, Cora; Sullivan, Aideen M.
• Is Part Of: Neuroscience letters. Volume 720(2020)
• Publication Date: 2020-02-16
• Subjects: E embryonic day -- FBS foetal bovine serum -- iPSC induced pluripotent stem cell -- MEF mouse embryonic fibroblast -- mDA midbrain dopamine -- PD Parkinson's disease -- PINK1 PTEN-induced putative kinase-1 -- VM ventral midbrain; α-Synuclein -- PINK1 -- Midbrain dopaminergic neurons -- Neurite growth -- Golgi fragmentation -- Mitochondrial fission; Neurology -- Periodicals; Neurology -- Periodicals; Research -- Periodicals; Neurologie -- Périodiques; Neuroanatomie -- Périodiques; Neuropharmacologie -- Périodiques; Neurophysiologie -- Périodiques; Neurology; Periodicals; Electronic journals; 617.48
• DOI: 10.1016/j.neulet.2020.134777
• Languages: English
• ISSNs: 0304-3940

Abstract

Highlights: α-synuclein overexpression reduces neurite length in cultured midbrain neurons. α-synuclein overexpression causes Golgi and mitochondria fragmentation in neurons. PINK1 knockdown causes Golgi and mitochondria fragmentation in neurons. PINK1 knockdown augments effects of α-synuclein overexpression on neurons. Abstract: Accumulation of α-synuclein is a pathological hallmark of Parkinson's disease (PD) and has been linked to reductions in neurite length and axonal degeneration of midbrain dopaminergic neurons. Mutations in SNCA, which encodes α-synuclein, and loss of function mutations in PTEN-induced putative kinase-1 ( PINK1 ) cause familial PD. There is a need to identify the mechanisms by which α-synuclein overexpression and the loss of PINK1 induce neurodegeneration in PD. To do this, we employed rat ventral midbrain cultures to investigate the effects of overexpression of wildtype or mutant (A53T) α-synuclein, and of siRNA knockdown of PINK1, on neurite length and on mitochondrial and Golgi integrity. We found reduced neurite length and increased levels of both Golgi fragmentation and mitochondrial fission in response to overexpression of wildtype or mutant α-synuclein, and to PINK1 knockdown. Reductions in neurite length induced by these two PD risk genes were significantly correlated with increases in Golgi fragmentation and mitochondrial fission. Combined α-synuclein overexpression and PINK1 knockdown induced a greater reduction in neurite length and increase in Golgi fragmentation, than either alone. This study provides novel evidence that α-synuclein overexpression and PINK1 deletion converge to induce significant increases in Golgi fragmentation and mitochondrial fission in midbrain neurons, that are correlated with decreases in neurite length. This highlights the need for further studies on these converging mechanisms in dopaminergic neurodegeneration in PD.