If Cellular Aging Is A Key Part Of Parkinson’s Disease Pathogenesis, How Do We Model It?
Parkinson’s Disease (PD) is a human disorder, and it is an age-related disorder. One of the big challenges to study PD-related mechanisms is access to live and aged cells that are either degenerating or inducing degeneration in the human brain. Access to model organisms has been instrumental to push forward our understanding of how brain cells interact and die in the context of PD. However, common animal models of the disease have much shorter lifespans than humans (~2-year lifespan for rodents and ~25-year lifespan for macaques). While it is difficult to determine which biological aspects of cellular aging are comparable in a 2-year-old mouse neuron vs. an 80-year-old human neuron, one can speculate that there exist temporal differences between species that contribute to the fact that old mice do not spontaneously develop PD, whereas some humans do as they age.
The brain is particularly impacted by aging because neurons are post-mitotic i.e., they do not divide and new neurons are not formed during adulthood except on very specific cases. Hence, the neuronal population is not replenished in cases of injury or disease. Evidence drawn from rodent studies suggests that aging also influences other cell type such as microglia – the brain resident immune cell – by downregulating genes that are important for the maintenance of microglial homeostasis as well as exacerbating the microglial response induced by an acute inflammatory stimulus. However, how aging affects brain cells at the molecular level in the context of PD is not known, and I believe that direct cell reprogramming will provide some answers.
The field of factor-mediated cell fate conversion was born with the demonstration that the forced expression of a myoblast-related transcription factor in fibroblasts transformed the cells towards the muscle cell lineage. This work led to the game-changing demonstration by the group of Shinya Yamanaka that the expression of four specific transcription factors were essential and sufficient to reprogram a terminally differentiated cell to a pluripotent stem cell. This ground-breaking work was especially important for the field of Neuroscience because it allowed for the first time to generate patient-specific neural cells in the lab to be used for regenerative medicine and disease modeling. These so-called induced pluripotent stem cells (iPSCs) have been incredibly useful in generating autologous neurons for cell-based-replacement therapy and are also providing fascinating insights into the disease-relevant mechanism of how some mutations lead to PD. However, preservation of human age as a major PD pathogenic risk factor is not occurring in these cells, given that they must transit through the embryo-like pluripotent state, which rejuvenates old somatic cells.
Inspired by the previous work done in the field of cell reprogramming, the group of Marius Wernig identified three neuronal fate inducing transcription factors able to convert mouse embryonic fibroblasts directly to neurons, that is without the pluripotent intermediate. In the years following this seminal demonstration, much work was done to improve the direct reprogramming process to generate specific neuronal and glial subtypes. More recently, a body of work showed that the process of direct reprogramming maintained key aspects of the cellular aging signature. This inspired us, when I was a post-doctoral fellow in the group of Malin Parmar, to develop an efficient protocol to be able to convert skin fibroblasts from PD patients to dopaminergic neurons that would maintain the aging signature of the parental cell. In these cells derived from idiopathic PD patients, we observe age-related protein degradation impairments that lead to the accumulation of the pathological form of alpha-synuclein. Interestingly, some impairments seen in induced neurons of PD patients are specific to the dopaminergic subtype. Thus, I believe that by circumventing the pluripotent state as well as any cell division, direct conversion preserves the cellular signatures of aging and that this is key to decipher what normal neuronal aging is, and when this is leading to PD. This could be instrumental in understanding at the molecular level the heterogeneity of idiopathic cases for which the only shared risk factor across all cases is age.
As our understanding of how best to reprogram adult fibroblasts to different cell type progresses, new reprogramming methods are surfacing to provide more complex model systems that will help shed light on how brain cells change their function and cell-to-cell interaction with aging, and how this relates to PD pathogenesis.
Janelle Drouin-Ouellet, PhD is Assistant Professor at the Faculty of Pharmacy of the University of Montreal and Canada Research Chair in Direct Neural Reprogramming. Dr. Drouin-Ouellet will be speaking about this topic as part of the WPC Research Spotlight series on Tuesday, November 15, 2022.
Ideas and opinions expressed in this post reflect that of the author solely. They do not reflect the opinions or positions of the World Parkinson Coalition®