Parkinson's disease is a considered to be caused by misfolding and aggregation of α-synuclein, a particularly pernicious malfunction of protein structure that can spread from cell to cell like a prion, encouraging other molecules of α-synuclein to also misfold in the same way. Mitochondria are prominently involved in Parkinson's disease because forms of impairment to mitochondrial function, whether by aging or inherited mutation, make the motor neurons in the brain that are already most vulnerable to death due to α-synuclein pathology even more vulnerable to that fate. Here, however, researchers turn this around, and provide evidence for a specific dysfunction in mitochondria to accelerate α-synuclein pathology. Biology is complex: both arrows of causation could be true, and both could be significant.
Mitochondrial dysfunction is a hallmark of Parkinson's disease (PD), but the mechanisms by which it drives autosomal dominant and idiopathic forms of PD remain unclear. To investigate this, we generated and performed a comprehensive phenotypic analysis of a knock-in mouse model carrying the T61I mutation in the mitochondrial protein CHCHD2 (coiled-coil-helix-coiled-coil-helix domain-containing 2), which causes late-onset symptoms indistinguishable from idiopathic PD.
We observed pronounced mitochondrial disruption in substantia nigra dopaminergic neurons, including distorted ultrastructure and CHCHD2 aggregation, as well as disrupted mitochondrial protein-protein interactions in brain lysates. These abnormalities were associated with a whole-body metabolic shift toward glycolysis, elevated mitochondrial reactive oxygen species (ROS), and progressive accumulation of aggregated α-synuclein.
In idiopathic PD, CHCHD2 gene expression also correlated with α-synuclein levels in vulnerable dopaminergic neurons, and CHCHD2 protein accumulated in early Lewy aggregates. These findings delineate a pathogenic cascade in which CHCHD2 accumulation impairs mitochondrial respiration and increases ROS production, driving α-synuclein aggregation and neurodegeneration.
Link: https://doi.org/10.1126/sciadv.adu0726
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