Could Subgrouping Parkinson’s Disease Using Cellular Phenotyping Enable Success at Clinical Trials?
Parkinson’s disease (PD) affects everyone differently. People with Parkinson’s display a wide range of motor and non-motor symptoms to differing degrees of severity and with varying responses to treatment. This diversity is termed clinical heterogeneity. A common issue seen within post-mortem brain samples is accumulation of proteins within the motor circuits of people with PD, although the exact reason for this remains unknown. However, other biological systems such as the energy system, waste and recycling pathways and the immune system also become dysfunctional during the course of disease. Targeting these systems with therapeutics may be a method for slowing or stopping the progression of disease, but like the various symptoms of Parkinson’s, individuals develop different issues within different pathways in their cells and brain, this is known as mechanistic heterogeneity.
Currently, researchers and clinicians subgroup PD into familial PD, referring to an inherited risk factor, or sporadic PD, defined as having no family history of PD. Depending on the population, familial PD accounts for between 5-15 % of all cases, but the exact genetic cause varies. Therefore, for much of the PD population we rarely know the underlying cause of disease. Thus, when clinical trials select a population of people with PD (PwP), it's uncertain whether the trial drug will address the specific issue in each participant's cells. Subgrouping PwP populations by the defective pathways within PwP cells may enable the selection of more effective clinical trial cohorts and ultimately personalised treatment plans in the clinic.
Interestingly, many of the problems observed in PwP brain cells can be identified in their skin cells, specifically in a type of cell known as fibroblasts. We are using PwP fibroblasts to subgroup a cohort of people with sporadic PD based on dysfunction in the energy and/or recycling pathways. We obtained skin biopsies from 35 people with sporadic PD and 23 neurologically healthy individuals. In order to assess the energy production system, we imaged and measured the function of the fibroblast’s mitochondria. Mitochondria are the battery of the cell; they convert sugars, fatty acids and proteins from food into an energy currency, called ATP, which powers the cell. We assessed lysosomes to understand the efficiency of the waste and recycling system. Broken and unwanted parts of the cell are transported to lysosomes, which break them down into usable building blocks for new functions. Two experiments, imaging the mitochondria and lysosomes and measuring ATP levels, enabled us to assess 10 markers of mitochondrial health and three markers of lysosomal health in our participants' cells. The cohort was then subdivided into small groups defined by patterns of dysfunction across the 13 health markers. In total we classified over 35% of our PD cohort into four distinct subgroups. One group was defined by problems with their mitochondria/energy system and one group defined by problems with their lysosomes/recycling system. Two groups were defined by a mix of problems in both the energy and recycling system, although the exact problems differed between these groups. For example, one mixed group had an increased number of poorly functioning mitochondria, while the other had a reduced number of mitochondria, each of these subgroups may represent different underlying problems that caused an individual’s Parkinson’s.
Further detailed investigation of these subgroups highlighted specific deficits in certain groups. Interrogation of the fibroblasts from the mitochondrial dysfunction group identified an inability to increase energy production when the demand is high, as the cells from healthy individuals are able to. This suggests that under ordinary circumstances, a PwP's mitochondria can efficiently match the ATP demand. But, when there is a high ATP demand, the PwP's energy system struggles to keep up. Investigation of the lysosomal subgroup found that PwPs had reduced activity by a protein cutting enzyme called Cathepsin D. This suggests that the lysosomes are unable to effectively break down cell components leading to further issues.
Fibroblasts are a great model of PD, however, to confirm that these deficits are still seen in a disease relevant cell type we are reprogramming cells from each subgroup into stem cells. These can be differentiated into dopaminergic neurons, the cell type that is affected in PD. We are currently investigating these induced dopaminergic neurons to understand the exact problems causing the differences between each subgroup and to trial a select set of therapeutics.
Toby Burgess PhD Student, Sheffield Institute for Translational Neuroscience, University of Sheffield, UK. He presented his work as part of a guided poster tour at the WPC 2023 in Barcelona.
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