Mitochondrial protein import stress potentiates neurodegeneration in a mouse model of Parkinson’s disease

Abstract

AbstractMitochondrial biogenesis depends on the import of cytosolically synthesized proteins, and many pathophysiological conditions are expected to reduce protein import. However, despite severe mitochondrial protein import defects concomitant with impaired oxidative phosphorylation being implicated in ultra-rare neurodegenerative diseases, the neurological effects specific to protein import stress are unknown due to lack of an adequate animal model. Here, we fill this gap using our recently established protein import “clogger” mouse model, which expresses mutant adenine nucleotide translocase 1 (Ant1) that clogs the mitochondrial protein import machinery. While a small fraction of clogger mice undergo paralytic neurodegeneration, we show that non-paralytic mice do not have bioenergetic defects in the central nervous system. Non-paralytic clogger mice actually perform better than wild-type in behavioral assays of motor coordination and executive function. Transcriptomic analysis revealed signaling pathways directed towards counteracting proteotoxicity, possibly as a response to the accumulation of mitochondrial preproteins in the cytosol, a process known as mitochondrial Precursor Overaccumulation Stress (mPOS). IGF-2 was robustly upregulated in the spinal cord. IGF-2 is known to play a role in the extrusion of cytosolic protein aggregates into the extracellular space, in addition to its primary role in cell growth and development. To provide further support for a role of protein import stress in neurodegeneration, we crossed the clogger mice with a mouse model of Parkinson’s disease expressing a cytosolic aggregation-prone protein, α-synucleinA53T. We found that mild protein import stress significantly worsens motor coordination in α-synucleinA53T, but not wild-type mice. In addition, double mutant mice showed modestly shortened maximal lifespan compared with α-synucleinA53T animals. We found no evidence of impaired bioenergetics in the double mutant mice. These findings suggest that mild protein import stress can modify neurodegeneration independent of bioenergetics. Future work is required to establish whether this occurs by enhancing cytosolic protein aggregation via mPOS.