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000633348 1001_ $$aAbdeen, Amr H.$$b0
000633348 245__ $$aParkinson-like wild-type superoxide dismutase 1 pathology induces nigral dopamine neuron degeneration in a novel murine model
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000633348 520__ $$aAtypical wild-type superoxide dismutase 1 (SOD1) protein misfolding and deposition occurs specifically within the degenerating substantia nigra pars compacta (SNc) in Parkinson disease. Mechanisms driving the formation of this pathology and relationship with SNc dopamine neuron health are yet to be fully understood. We applied proteomic mass spectrometry and synchrotron-based biometal quantification to post-mortem brain tissues from the SNc of Parkinson disease patients and age-matched controls to uncover key factors underlying the formation of wild-type SOD1 pathology in this disorder. We also engineered two of these factors - brain copper deficiency and upregulated SOD1 protein levels - into a novel mouse strain, termed the SOCK mouse, to verify their involvement in the development of Parkinson-like wild-type SOD1 pathology and their impact on dopamine neuron health. Soluble SOD1 protein in the degenerating Parkinson disease SNc exhibited altered post-translational modifications, which may underlie changes to the enzymatic activity and aggregation of the protein in this region. These include decreased copper binding, dysregulation of physiological glycosylation, and atypical oxidation and glycation of key SOD1 amino acid residues. We demonstrated that the biochemical profile introduced in SOCK mice promotes the same post-translational modifications and the development of Parkinson-like wild-type SOD1 pathology in the midbrain and cortex. This pathology accumulates progressively with age and is accompanied by nigrostriatal degeneration and dysfunction, which occur in the absence of α-synuclein deposition. These mice do not exhibit weight loss nor spinal cord motor neuron degeneration, distinguishing them from transgenic mutant SOD1 mouse models. This study provides the first in vivo evidence that mismetallation and altered post-translational modifications precipitates wild-type SOD1 misfolding, dysfunction, and deposition in the Parkinson disease brain, which may contribute to SNc dopamine neuron degeneration. Our data position this pathology as a novel drug target for this disorder, with a particular focus on therapies capable of correcting alterations to SOD1 post-translational modifications. 
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000633348 7001_ $$aTrist, Benjamin G.$$b1
000633348 7001_ $$aNikseresht, Sara$$b2
000633348 7001_ $$aHarwood, Richard$$b3
000633348 7001_ $$0P:(DE-H253)PIP1031511$$aRoudeau, Stéphane$$b4
000633348 7001_ $$aRowlands, Benjamin D.$$b5
000633348 7001_ $$aKreilaus, Fabian$$b6
000633348 7001_ $$aCottam, Veronica$$b7
000633348 7001_ $$aMor, David$$b8
000633348 7001_ $$aRichardson, Miriam$$b9
000633348 7001_ $$aSiciliano, Joel$$b10
000633348 7001_ $$aForkgen, Julia$$b11
000633348 7001_ $$aSchaffer, Greta$$b12
000633348 7001_ $$aGenoud, Sian$$b13
000633348 7001_ $$aLi, Anne A.$$b14
000633348 7001_ $$aProschogo, Nicholas$$b15
000633348 7001_ $$aAntonio, Bernadeth$$b16
000633348 7001_ $$0P:(DE-H253)PIP1002716$$aFalkenberg, Gerald$$b17
000633348 7001_ $$0P:(DE-H253)PIP1021825$$aBrueckner, Dennis$$b18
000633348 7001_ $$aKysenius, Kai$$b19
000633348 7001_ $$aLiddell, Jeffrey R.$$b20
000633348 7001_ $$aFat, Sandrine Chan Moi$$b21
000633348 7001_ $$aWu, Sharlynn$$b22
000633348 7001_ $$aFifita, Jennifer$$b23
000633348 7001_ $$aLockwood, Thomas E.$$b24
000633348 7001_ $$aBishop, David P.$$b25
000633348 7001_ $$aBlair, Ian$$b26
000633348 7001_ $$0P:(DE-H253)PIP1010711$$aOrtega, Richard$$b27
000633348 7001_ $$aCrouch, Peter J.$$b28
000633348 7001_ $$0P:(DE-H253)PIP1085626$$aDouble, Kay$$b29$$eCorresponding author
000633348 773__ $$0PERI:(DE-600)1458410-4$$a10.1007/s00401-025-02859-6$$gVol. 149, no. 1, p. 22$$n1$$p22$$tActa neuropathologica$$v149$$x0001-6322$$y2025
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