Mitochondrial dysfunction has long been observed in Parkinson’s Disease (PD) patient brains, but how this causes or contributes to neurodegeneration in PD is much less clear. In their recent Science Advances article, BARI member Ken Nakamura and his lab studied the mitochondrial intermembrane space protein CHCHD2 to offer new in vivo insights into this pathogenic cascade.
Recapitulating a human CHCHD2 mutation in mice leads to discovery
In 2015, an inherited form of late-onset Parkinson’s disease (PD) was first reported to be caused by mutations in the mitochondrial protein CHCHD2, thereby establishing that mitochondrial dysfunction can cause a form of PD that is clinically indistinguishable from sporadic PD. However, the mechanisms by which CHCHD2 mutations produce PD are unknown, and CHCHD2 mouse knock-outs present with mild phenotypes, suggesting that a simple loss of the protein is not responsible for causing the human disease. To better understand the pathophysiology, Liao et al. used CRISPR-Cas9 to generate a mouse model with the T61I point mutation (T61I) in CHCHD2.
Like many other age-induced neurodegenerative disease models in short-lived mice, the motor deficits were only subtly disrupted with age. However, a closer look revealed that the dopaminergic neurons in mutant mice showed early signs of mitochondrial damage and abnormal behavior of the T61I CHCHD2 protein. For example, super-resolution microscopy showed increased puncta of CHCHD2 and its heterodimer partner CHCHD10 in dopaminergic neurons in the substantia nigra pars compacta (SNc) of mutant mice by 9 months that was more evident with increasing age. These aggregates were predominantly localized within mitochondria, and electron microscopy revealed mitochondria swelling in T61I CHCHD2 homozygotes. Considering the high energy demands of dopaminergic neurons for normal function, the authors hypothesized that progressively increasing numbers of swollen, unhealthy mitochondria might lead to eventual neurodegeneration.
T61I CHCHD2-induced mitochondrial dysfunction leads to a metabolic shift
In addition to the mitochondria structural changes, Nakamura and team also found evidence that the T61I point mutation in CHCHD2 leads to mitochondrial energy metabolism differences. Mutant mouse brains shifted toward increased reliance on glycolysis for energy, suggesting that mitochondrial respiration is unable to supply sufficient energy to accommodate the demands of the brain. In support of this hypothesis, there was less expression of respiratory chain genes in mutant DA neurons, and many mitochondrial protein-protein interactions were disrupted. Mitochondrial ROS was also found to increase substantially with age, beginning at 11 months in T61I homozygous mice. The team identified the striking finding that 333 proteins in the mitochondria of mutant mouse brains lost their usual interactions with partner proteins, the majority of which involved PD-associated proteins such as Prdx2, Park7, and Sod2. This is the first evidence to date that disrupted ROS-regulatory protein-protein interactions result in excess ROS in CHCHD2 T61I mutant mice, which the team hypothesizes may be due to the presence of CHCHD2 aggregates in the mitochondrial space.
Mutant CHCHD2 causes α-synuclein aggregation
The team found that CHCHD2 and α-synuclein protein colocalized in SNc dopaminergic neurons at all stages of Lewy body development, the pathological hallmark, in human PD samples. In their CHCHD2 T61I mutant mice, aggregated α-synuclein was detected by 17 months and increased with age. However, this aggregation arises subsequent to the increased oxidative stress by several months, contributing to the author’s hypothesis that mutation-induced ROS may be a key driver of α-synuclein aggregation, and that mutant CHCHD2 produces toxicity in part through the accumulation of toxic α-synuclein. While there is still more work to be done, the Nakamura lab is hopeful that their study will provide a foundation for understanding how mitochondrial dysfunction can cause PD, and that ultimately new treatments can be identified.
What’s next for the Nakamura lab?
With a deeper understanding of how the T61I mutation in CHCHD2 disrupts mitochondrial function and contributes to Parkinson's disease-like pathology, the Nakamura team is now focused on elucidating the precise mechanisms by which these effects, particularly elevated reactive oxygen species (ROS) and energy failure, drive cellular toxicity in dopaminergic neurons. Building on their findings, they also plan to investigate whether CHCHD2 plays a similar role in the more common sporadic forms of the disorder. Ultimately, the lab aims to leverage these insights to develop targeted therapeutic strategies that maintain or boost CHCHD2 function or mitigate its downstream impacts on mitochondrial health and α-synuclein aggregation. This forward-looking work holds promise for bridging mitochondrial biology with practical interventions, potentially transforming treatment options for Parkinson's patients.