Peer-Reviewed Journal Details
Mandatory Fields
Furlong R.;O'Keeffe G.;O'Neill C.;Sullivan A.
2020
February
Neuroscience Letters
Alterations in a-synuclein and PINK1 expression reduce neurite length and induce mitochondrial fission and Golgi fragmentation in midbrain neurons
Validated
WOS: 7 ()
Optional Fields
Golgi fragmentation Midbrain dopaminergic neurons Mitochondrial fission Neurite growth PINK1 a-Synuclein
720
2020 Elsevier B.V. Accumulation of a-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 a-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 a-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) a-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 a-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 a-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 a-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.
0304-3940
10.1016/j.neulet.2020.134777
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