Objective: To identify a new therapeutic target for developing neuroprotective treatment in Parkinson’s disease (PD) by improving mitochondrial function through restoration of mitochondrial quality control system.

Background: PD is the second most common neurodegenerative disorder worldwide. Loss of Parkin or PINK1 abrogates mitochondrial quality control (i.e. impaired PINK1/Parkin mitophagic pathway), leading to accumulation of dysfunctional mitochondria and autosomal recessive early-onset PD. Previously, we have identified a homozygous Parkin mutation carrier who has not developed PD by her eighth decade despite Parkin deficiency1. The underlying protective mechanism remained unclear.

Methods: We analyzed mitochondrial function and mitophagy in cell models derived from the asymptomatic carrier. We then confirmed the presence of an alternative mitophagic pathway in the asymptomatic carrier. Genetic and pharmacological induction of the alternative mitophagic pathway was carried out in four other PINK1/Parkin-deficient patient cell lines and changes in their mitochondrial phenotypes were examined.

Results: The asymptomatic carrier cells had normal mitochondrial function and quality control. In these cells, we identified an alternative mitophagic pathway which facilitates the maintenance of mitochondrial quality control and function in a Parkin-independent manner. Genetic inactivation of this pathway resulted in a loss of mitophagy in the asymptomatic carrier cells, while induction of the pathway restored mitophagy and improved mitochondrial function in the PINK1/Parkin-deficient patient cells.

Conclusions: These findings support the potential use of activating an alternative mitophagic pathway to compensate for the loss of PINK1/Parkin-mediated mitophagy, thereby maintaining normal mitochondrial quality and function. Our study highlights a new therapeutic target that can provide a neuroprotective intervention in mitophagy-compromised PD patients by restoring the mitochondrial quality control system. 1. Koentjoro B, Park JS, Ha AD, Sue CM. Phenotypic variability of parkin mutations in single kindred. Mov Disord 2012;27(10):1299-1303.

« Back to 2016 International Congress

MDS Abstracts - https://www.mdsabstracts.org/abstract/counteracting-pink1parkin-deficiency-by-activating-alternative-mitophagic-pathway-a-potential-therapeutic-intervention-for-parkinsons-disease/