Abstract
Parkinson disease (PD) is the second most common neurodegenerative disorder and the leading neurodegenerative cause of motor disability. Pathologic accumulation of aggregated alpha synuclein (AS) protein in brain, and imbalance in the nigrostriatal system due to the loss of dopaminergic neurons in the substantia nigra- pars compacta, are hallmark features in PD. AS aggregation and propagation are considered to trigger neurotoxic mechanisms in PD, including mitochondrial deficits and oxidative stress. The eukaryotic elongation factor-2 kinase (eEF2K) mediates critical regulation of dendritic mRNA translation and is a crucial molecule in diverse forms of synaptic plasticity. Here we show that eEF2K activity, assessed by immuonohistochemical detection of eEF2 phosphorylation on serine residue 56, is increased in postmortem PD midbrain and hippocampus. Induction of aggressive, AS-related motor phenotypes in a transgenic PD M83 mouse model also increased brain eEF2K expression and activity. In cultures of dopaminergic N2A cells, overexpression of wild-type human AS or the A53T mutant increased eEF2K activity. eEF2K inhibition prevented the cytotoxicity associated with AS overexpression in N2A cells by improving mitochondrial function and reduced oxidative stress. Furthermore, genetic deletion of the eEF2K ortholog efk-1 in C. elegans attenuated human A53T AS induced defects in behavioural assays reliant on dopaminergic neuron function. These data suggest a role for eEF2K activity in AS toxicity, and support eEF2K inhibition as a potential target in reducing AS-induced oxidative stress in PD.
Highlights
Parkinson disease (PD) is the most common neurodegenerative cause of motor disability and is estimated to affect around 10 million people worldwide [33, 53]
In parallel, using serial sections, we assessed the phosphorylation of alpha synuclein (AS) on serine residue 129 (p-ASyn, S129) by IHC, as it is a robust marker for AS Lewy pathology (~ 90% S129 phosphorylated AS is found in inclusions) [2, 65]
To avoid ambiguity with neuromelanin pigment found in dopaminergic neurons in substantia nigra (SN) with DAB IHC staining, we employed a modified IHC protocol [52] in order to effectively destain/bleache neuromelanin in midbrain sections without adversely affecting p-eukaryotic elongation factor-2 (eEF2) (T56) IHC staining (Additional file 1: Figure S1a-b)
Summary
Parkinson disease (PD) is the most common neurodegenerative cause of motor disability and is estimated to affect around 10 million people worldwide [33, 53] It presents as a movement disorder characterized by resting tremor, rigidity, and bradykinesia, and in a substantial number of patients the motor disability is. Missense mutations in SNCA resulting in N-terminal amino acid substitutions in the AS protein, or multiplications in SNCA gene locus leading to increased AS expression are the earliest known causes of autosomal-dominant inherited forms of PD [53, 54, 62]. Autosomal-dominant mutations in leucine-rich repeat kinase 2 (LRRK2), which account for the most common cause of inherited PD [53], are associated with defective autophagy and mitochondrial dysfunction [68]. Exposure to several chemical toxins that inhibit complex I is well documented to induce dopaminergic neuron degeneration and a parkinsonian phenotype in humans (e.g., 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, MPTP) and in animals (e.g., MPTP, rotenone, paraquat etc.) [33, 59]
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