One of the greatest challenges in understanding Parkinson’s disease (PD) is how little we know about the origins and development of the condition. Our studies of postmortem tissue are like examining the result of a car crash and attempting to deduce what precipitated the accident and how it occurred. We only get to directly observe the end result of PD since acquiring live biopsies from human patients during the course of the disease is impossible.

One solution to this dilemma is to study PD using stem cell technology. For our research, published in January in Nature Medicine, we generated special stem cells, known as induced pluripotent stem cells (iPSCs), from cells of patients with young-onset PD. This process involved taking adult blood cells "back in time" to an embryonic state.

Our team used the iPSCs to produce dopamine neurons from each patient and then cultured them in a dish and analyzed the neurons' functions. These neurons were genetically identical to the patients' own neurons. We compared these neurons to those of a control group of individuals without young-onset PD.

I was co-first author of this study, along with project scientist Samuel Sances, PhD, and project scientist Nur Yucer, PhD, both from Cedars-Sinai. The senior author was Clive Svendsen, PhD, director of the Cedars-Sinai Board of Governors Regenerative Medicine Institute.

Among our findings:

• Elevated levels of alpha synuclein in the cells of 11 of the 12 patients in the study, This protein occurs in most forms of PD. Importantly, none of the 10 control lines showed a similar elevation of alpha synuclein. This finding suggests that defects in alpha synuclein handling could be a common feature in PD and highlights therapies that target reducing alpha synuclein levels as having the potential to modify the disease.

• Lysosomal dysregulation. Lysosomes are cell structures that act as "trash cans" to break down and dispose of proteins. Our study's results suggest that alpha synuclein is primarily degraded through lysosomal means in dopamine neurons and that dysregulation of these same lysosomal proteins is another common feature in both sporadic and inherited PD.

• A drug that can promote alpha synuclein degradation. Introducing a drug called PEP005 resulted in a reduction of alpha synuclein levels in both control and young-onset PD cultures of dopamine neurons. PEP005 is currently FDA approved for the treatment of a different condition, actinic keratosis.

• Elevated levels of the protein kinase PKC alpha, a main binding partner of PEP005, in young-onset PD cultures. This was our most consistent and specific marker for identifying these patients.

Overall, our findings suggest that there must be a significant and unknown genetic component to young-onset PD. Studies examining the genetic burden in this patient population would help identify these likely diverse pathways and potentially might lead to new genetic screens and therapeutic targets for this condition.

The molecular signature we’ve identified in our iPSC model could also be used as a screening tool to diagnose patients with young-onset PD or those likely to develop it.

Finally, our iPSC model of sporadic PD gives us the opportunity to test drugs with the goal of altering the underlying mechanisms of this disease. Testing of more extensive pharmaceutical libraries could help identify new drugs that alter these molecular disease signatures.

Alexander Laperle, PhD is a project scientist at the Cedars-Sinai Board of Governors Regenerative Medicine Institute in Los Angeles.

This research was first shared as an abstract at the WPC 2019 in Kyoto. WPC is pleased to support abstract authors by sharing their ongoing work. Digital files of WPC abstract books can be downloaded from the past three Congresses HERE.

Ideas and opinions expressed in this post reflect that of the author(s) solely. They do not necessarily reflect the opinions of the World Parkinson Coalition®