ADP/ATP translocase 1 protects against an α-synuclein-associated neuronal cell damage in Parkinson’s disease model

Abstract

Background ADP/ATP translocase 1 (ANT1) is involved in the exchange of cytosolic ADP and mitochondrial ATP, and its defection plays an important role in mitochondrial pathogenesis. To reveal an etiological implication of ANT1 for Parkinson’s disease (PD), a neurodegenerative disorder, a mouse model treated with 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine and neuroblastoma cell model induced by 1-methyl-4-pehny1-pyridine were utilized in this study. Results The tissue-specific abundance in ANT1 in mouse brains was accessed using the analysis of Western blot and immunohistochemistry. Down-regulated soluble ANT1 was found to be correlated with PD, and ANT1 was associated with PD pathogenesis via forming protein aggregates with α-synuclein. This finding was confirmed at cellular level using neuroblastoma cell models. ANT1 supplement in neuronal cells revealed the protective roles of ANT1 against cytotoxicity caused by MPP+. Protein interaction assay, coupled with the analysis of LC-MS/MS, silver-stained SDS-PAGE and Western blot against anti-ANT1 antibody respectively, illustrated the interaction of ANT1 with α-synuclein using the expressed α-synuclein as a bite. Additionally, a significant increasing ROSs was detected in the MPP+-treated cells. Conclusions This study indicated that ANT1 was a potentially causative factor of PD, and led to neuropathogenic injury via promoting the formation of protein aggregates with α-synuclein. This investigation potentially promotes an innovative understanding of ANT1 on the etiology of PD and provides valuable information on developing potential drug targets in PD treatment or reliable biomarkers in PD prognostication.

In‐depth analysis of the Sirtuin 5‐regulated mouse brain malonylome and succinylome using library‐free data‐independent acquisitions

“…In PD, lower levels of ANT1 leads to mPTP being open, triggering a cascade of cell apoptosis program. Moreover, ANT1 co-aggregates with α -synuclein, potentially causing neuronal damages [ 81 ].…”

Adenine nucleotide translocase: Current knowledge in post‐translational modifications, regulations and pathological implications for human diseases

“…In PD mouse model, a deficiency in ANT1 abundance and formation of a protein coaggregation containing αsynuclein and ANT1 are found specifically in animal models with PDlike variation. 93 In addition, the protein coaggregation composing of αsynuclein and ANT1 had been detected in neuroblastoma cells which was treated with MPP + as well (Figure 5B). ANT1 is associated with mitochondriopathy related to PD, since ANT1 mutation leads to permanent mPTP opening, elevated ROS product, and an active CytC-related pathway in MPP + -treated neuroblastoma cells.…”

“…Mostly importantly, our recent study shows that ANT1 is associated with high risk of PD. In PD mouse model, a deficiency in ANT1 abundance and formation of a protein coaggregation containing α‐synuclein and ANT1 are found specifically in animal models with PD‐like variation 93 . In addition, the protein coaggregation composing of α‐synuclein and ANT1 had been detected in neuroblastoma cells which was treated with MPP + as well (Figure 5B).…”

“…Therefore, an extensive socioeconomic burden worldwide associated with PD is expected as the world population ages. 92,93 It is found that ATR has a synergistic effect on mPTP opening of the neuronal cells with MPP + , which is the degraded and active form of MPTP (1-Methyl-4-phenyl -1,2,3,6-tetrahydropyridine) inside cells. Usually, MPTP is a worldwide-used agent for preparing animal models with essential Parkinsonian symptoms.…”

“…Especially, a longer survival of the aged persons caused by a current improvement in health care, finally may result in a continuous rise in the number of PD patients over time. Therefore, an extensive socioeconomic burden worldwide associated with PD is expected as the world population ages 92,93 …”