An antioxidant and anti-ER stress combination therapy elevates phosphorylation of α-Syn at serine 129 and alleviates post-TBI PD-like pathology in a sex-specific manner in mice

Charles K Davis; Saivenkateshkomal Bathula; Soomin Jeong; Vijay Arruri; Jeongwoo Choi; Shruti Subramanian; Carlie M Ostrom; Raghu Vemuganti

doi:10.1016/j.expneurol.2024.114795

An antioxidant and anti-ER stress combination therapy elevates phosphorylation of α-Syn at serine 129 and alleviates post-TBI PD-like pathology in a sex-specific manner in mice

Exp Neurol. 2024 Apr 23:377:114795. doi: 10.1016/j.expneurol.2024.114795. Online ahead of print.

Authors

Charles K Davis¹, Saivenkateshkomal Bathula¹, Soomin Jeong², Vijay Arruri¹, Jeongwoo Choi¹, Shruti Subramanian¹, Carlie M Ostrom¹, Raghu Vemuganti³

Affiliations

¹ Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA.
² Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin, Madison, WI, USA.
³ Department of Neurological Surgery, University of Wisconsin, Madison, WI, USA; Neuroscience Training Program, University of Wisconsin, Madison, WI, USA; William S. Middleton Memorial Veterans Hospital, Madison, WI, USA. Electronic address: vemuganti@neurosurgery.wisc.edu.

PMID: 38657855
DOI: 10.1016/j.expneurol.2024.114795

Abstract

Clinical studies have shown that traumatic brain injury (TBI) increases the onset of Parkinson's disease (PD) in later life by >50%. Oxidative stress, endoplasmic reticulum (ER) stress, and inflammation are the major drivers of both TBI and PD pathologies. We presently evaluated if curtailing oxidative stress and ER stress concomitantly using a combination of apocynin and tert-butylhydroquinone and salubrinal during the acute stage after TBI in mice reduces the severity of late-onset PD-like pathology. The effect of multiple low doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on post-TBI neurodegeneration was also evaluated. The combo therapy elevated the level of phosphorylation at serine 129 (pS129) of α-Syn in the pericontusional cortex of male mice at 72 h post-TBI. Motor and cognitive deficits induced by TBI lasted at least 3 months and the combo therapy curtailed these deficits in both sexes. At 3 months post-TBI, male mice given combo therapy exhibited significantly lesser α-Syn aggregates in the SN and higher TH+ cells in the SNpc, compared to vehicle control. However, the aggregate number was not significantly different between groups of female mice. Moreover, TBI-induced loss of TH+ cells was negligible in female mice irrespective of treatment. The MPTP treatment aggravated PD-like pathology in male mice but had a negligible effect on the loss of TH+ cells in female mice. Thus, the present study indicates that mitigation of TBI-induced oxidative stress and ER stress at the acute stage could potentially reduce the risk of post-TBI PD-like pathology at least in male mice, plausibly by elevating pS129-α-Syn level.

Keywords: ER stress; MPTP; Neurodegeneration; Oxidative stress; PD-like pathology; TBI; α-Syn.