NEW, INNOVATIVE PARKINSON’S DISEASE RESEARCH BEING FUNDED BY APDA

On September 1, 2021, APDA announced our research grantees for the year ahead. Our grant recipients are working tirelessly to understand the complexities of Parkinson’s disease in an effort to develop new treatments and eventually, a cure, and we are honored to support their work. This year APDA awarded $1.85 million in grants that will support a wide range of fascinating research.

The APDA Scientific Advisory Board thoroughly vetted each application and chose these grantees very carefully. While the science can seem complicated and the medical jargon confusing, rest assured that this work is not only significant, but exciting as well. Below, I present the research projects APDA will be funding and point out why they are important for the PD community. You can click on any of the researchers below to learn more about them and their work.

The 2021-2022 APDA Parkinson’s Research Grants:

The George C. Cotzias Fellowship

This is APDA’s most prestigious grant and is awarded to a young physician-scientist with exceptional promise who is establishing a career in research, teaching, and clinical services relevant to Parkinson’s. The award spans three years and is designed to fund a long-range project focused on PD. This year’s awardee is:

Abby L. Olsen, MD, PhD
The Brigham and Women’s Hospital
Harnessing the untapped therapeutic potential of glia in Parkinson’s disease

Major question to be answered: Which genes in glial cells (the brain’s helper cells) are important in PD? 

Why is this important? The glial cells are not well-studied in PD, yet they perform many essential brain functions. By increasing the understanding of the role of these cells in PD, new possible therapeutic targets can be identified.

Glial cells represent approximately half of all cells in the human brain and perform many essential functions to allow the neurons to work. Many PD risk genes have been identified, and the majority of these genes are expressed (turned on) in glia. This suggests that glia may contribute to risk and progression of PD. In spite of this, glia have been understudied as a source of possible therapeutic targets for PD. By using a fruit fly model of PD, this project seeks to identify new genes in glia that may be good targets for drug therapy.

 

APDA Diversity in Parkinson’s Disease Research Grants

These are one-year grants to study the health inequities and/or differences among under-studied PD communities, across the spectrum of ethnicity, ancestry, geography, socioeconomic conditions, and gender. The two awardees are:

Jennifer G. Goldman, MD, MS
Shirley Ryan AbilityLab
Understanding utilization of rehabilitation services across diverse populations

Major question to be answered:  What are the rehabilitation care needs and utilization in PD across diverse populations? 

Why is this important?  The project aims to understand the factors that affect access, delivery, and utilization of rehabilitation care in PD, in order to address healthcare disparities, partner with communities, and provide quality rehabilitation care for more people with PD.

PD symptoms such as loss of balance, falls, reduced dexterity, tremor, dysphagia, and cognitive decline have substantial impact on quality of life, work, self-care, and clinical outcomes. Many of these symptoms are therapeutic target areas for rehabilitation care by physical therapy, occupational therapy, and speech language pathology. Rehabilitation therapies can improve functional abilities and quality of life and reduce complications such as falls and fracture risk. However, healthcare disparities have been found in Parkinson’s rehabilitation care regarding referrals and utilization, among other aspects. This study will examine disparities in referrals, access, availability, and use of rehabilitation care in African Americans with PD, understand the specific needs of this community, and identify how to address gaps in quality care.

Miguel E. Rentería, PhD
Red Mexicana de Bioinformática
Clinical, epidemiological, and cognitive characterization of Parkinson’s disease in the Mexican population

Major question to be answered:  What are the clinical, cognitive, epidemiological, social, and genetic characteristics of people with PD in Mexico? 

Why is this important?  PD has mostly been studied in European populations. In order to broaden our understanding of PD, under-represented populations with PD need to be characterized. 

Although PD affects individuals from all ethnic groups, most of our current understanding of the etiology, pathophysiology, phenotypic diversity, and progression of PD comes from research in European ancestry participants from the USA and Europe, but growing evidence suggests that ethnicity and ancestry, as well as social and environmental factors, are associated with differences in PD epidemiology, clinical manifestations, and mortality. Therefore, it is crucial to adequately characterize diverse groups of PD patients to understand the underlying causes of those differences. This study seeks to fully characterize a Mexican population of people with PD.

 

Post-Doctoral Fellowships

The grants are awarded to support post-doctoral scientists, who recently completed their PhD work, and whose research holds promise to provide new insights into the pathophysiology, etiology, and treatment of Parkinson’s disease. This year’s awardees are:

Rachel A. Coleman, PhD
University of Alabama at Birmingham
LRRK2 regulation of glucocerebrosidase activity: role of Rab10 and pathological characterization

Major question to be answered:  How do LRRK2 and GCase work together to increase risk of PD?

Why is this important? By understanding the relationship between LRRK2 and glucocerebrosidase (GCase), new therapeutic interventions may be discovered.
A number of different gene mutations have been identified that increase an individual’s risk of developing PD. These gene mutations often result in abnormal activity of specific proteins, which contribute to disease development, but it is unclear how these proteins interact with each other. A recent study identified a regulatory mechanism between two proteins, LRRK2 and GCase, that are each known to be independently linked to PD. This study will further probe this interaction to increase our understanding of the relationship between LRRK2 and GCase.

By understanding the relationship between LRRK2 and glucocerebrosidase (GCase), new therapeutic interventions may be discovered.
A number of different gene mutations have been identified that increase an individual’s risk of developing PD. These gene mutations often result in abnormal activity of specific proteins, which contribute to disease development, but it is unclear how these proteins interact with each other. A recent study identified a regulatory mechanism between two proteins, LRRK2 and GCase, that are each known to be independently linked to PD. This study will further probe this interaction to increase our understanding of the relationship between LRRK2 and GCase.

Enrico Opri, PhD
Emory University
DBS-induced local evoked potentials for asleep intraoperative functional mapping

Major question to be answered: Can deep brain stimulation (DBS) surgical targeting and implantation be improved by using a new neurophysiological signal named DBS local evoked potentials (DLEPs)?

Why is this important? Improving brain mapping (based on DLEP) during DBS surgery may improve DBS outcomes during asleep surgery. One of the most important factors to ensure the best therapeutic effect and minimize side effects of DBS, is the correct placement of the leads within the target brain region. Currently, one of the preferred techniques to find the DBS target region is the use of microelectrode recordings (MER) of neural activity during the surgery, a process also known as functional mapping. This modality requires the patient to be awake, and participate actively during the surgery, which may lead to anxiety and discomfort.
An alternative surgical approach that addresses some of these challenges is intraoperative magnetic resonance imaging (iMRI), where implantation is based on real-time imaging of both the brain and the lead location. However, iMRI implantations may be hampered by poorly-defined target borders. As a result, there is a need for physiologic mapping in “asleep” surgeries.

Recent studies have proposed a novel neurophysiological signal, named DBS local evoked potentials (DLEPs). DLEPs can be elicited under moderate anesthesia, require no patient interaction, are potentially easier to detect compared to other electrophysiological markers used currently in surgical functional mapping, and can be recorded directly from the implanted DBS leads. This study will seek to assess the feasibility and accuracy of the DLEP-based localization in estimating and validating the optimal DBS target location, comparing it with the imaging-only based approach and the MER approach.

Leonardo Parra-Rivas, PhD
University of California San Diego
Evaluating α-synuclein pathophysiology in human neurons

Major question to be answered: What is the pathophysiologic role of α-synuclein in human neurons?

Why is this important?  Understanding the normal function of α-synuclein and its role during disease progression is essential for the development of new therapies for PD.
There is significant evidence supporting the involvement of α-synuclein in PD. Aggregation of α-synuclein in neurons, is the neuropathologic hallmark of PD. Moreover, α-synuclein mutations can be seen in familial disease, where the severity of PD seems to be dependent on how many mutated copies of α-synuclein are present. Given this, there has been a significant effort to understand the normal function of α-synuclein, but despite research spanning almost two decades, there is still no clear answer. Another major caveat to the understanding of α-synuclein function is that essentially all experiments have been done in mouse models or mouse neurons, and α-synuclein function in human neurons is therefore poorly understood. This project will use genome-editing techniques to deplete or activate α-synuclein, along with optical and electrophysiologic assays, to study neuronal function in human induced pluripotent stem cell (IPSC)-derived neurons.

 

Research Grants

Our research grants are awarded to investigators performing innovative Parkinson’s disease research at major academic institutions across the United States. This year’s awardees are: 

Constanza J. Cortes, PhD
University of Alabama at Birmingham
Exercise-Mimetics: novel neuroprotectant pathways in Parkinson disease

Major question to be answered:   What are the molecular underpinnings of the neuroprotective effects of exercise?

Why is this important? Studies into the neuroprotective effects of exercise will help to define therapies that harness these effects to benefit people with PD.
Physical activity has extensive and well-documented neuroprotective effects, benefitting cognitive function during healthy aging and reducing the risk of age-associated neurodegenerative disorders, including PD. The mechanisms responsible for the brain benefits of exercise, however, remain largely unexplored. This project tests the hypothesis that exercise can reduce PD-associated pathology in the brain, using behavioral exercise interventions in mice. The project will also introduce PD pathology into unique transgenic mice that are engineered to display neuroprotective effects and determine if these mice can withstand PD pathology more than wild type mice.

Xianjun Dong, PhD
The Brigham and Women’s Hospital
Developing RNA biomarkers of early PD pathology from brain organoids and extracellular vesicles

Major question to be answered:  Can RNA biomarkers be identified for detection of early PD pathology?

Why is this important? This study aims to develop better ways of diagnosing PD and further our understanding of how PD develops. Induced pluripotent stem cells (iPSC) from patients with penetrant familial PD mutations are a promising model for the study of early brain processes that occur in PD. 3D brain organoids have recently been generated using iPSCs to model PD. Organoids offer the advantage of providing a more physiological environment that mimics the brain, since they display an organized structure and consist of multiple cell types on a spectrum of cellular maturity. The organoid functions as a mini-brain and can be used for many purposes, including the study of potential biomarkers. One source of potential biomarkers that is produced by the organoids are extracellular vesicles (EV) that contain ribonucleic acid (RNA). This study investigates the RNAs contained in the EVs in order to both identify potential RNA biomarkers and further the understanding of the events that lead to development of PD.

Rebekah Evans, PhD
Georgetown University
Defining circuit alterations that influence dopaminergic neuron vulnerability in early Parkinson’s disease

Major question to be answered:  How does neurodegeneration in the pedunculopontine nucleus (PPN) increase dopaminergic neuron vulnerability?

Why is this important?  Understanding how early degeneration of non-dopaminergic brain structures can alter the vulnerability of dopaminergic neurons is a first step toward developing circuit-based therapies to slow the progression of PD through the brain.
PD progresses through the brain from region to region. The mechanisms of this progression are an area of active research, but how PD ultimately reaches the dopaminergic neurons remains unknown. The pedunculopontine nucleus (PPN) degenerates in PD and contains neurons which connect directly to the dopaminergic neurons. Lesions of certain subsets of PPN neurons can cause dopaminergic degeneration and can recapitulate symptoms of early PD. Currently, it is not understood how neurodegeneration in the PPN increases dopaminergic neuron vulnerability. In this study, the cholinergic neurons of the PPN will be lesioned and then the cellular and circuit-level changes that occur in dopaminergic neurons will be measured in order to determine how PPN degeneration may contribute to development of PD. 

Rafiq Huda, PhD
Rutgers University
Harnessing astrocyte neuromodulation for alleviating the motor symptoms of Parkinson’s disease

Major question to be answered:  Are astrocytes, a cell type in the brain that supports various functions of the neurons, critical in the neural circuity that controls movement?

Why is this important?   This study will establish novel roles for astrocytes in the control of brain circuits known to be affected in PD, paving the way for next-generation astrocyte-targeted therapies for PD.
Astrocytes have highly-branched processes that surround neurons and the connections between neurons called synapses. They are known to modify and influence synaptic transmission and neuronal activity. However, it is unknown how astrocytes specifically contribute to motor control and how dopamine loss changes the function of astrocytes. We hypothesize that dopamine loss is associated with reduced astrocyte calcium signaling, which compromises neuronal network activation during movement. Therefore, augmenting astrocyte calcium may improve motor function in PD. We will aim to show that astrocyte calcium signaling can be harnessed to alleviate the motor symptoms of PD in a mouse model of PD.

Sunil Kumar, PhD
University of Denver
Identification of novel targets associated with α-synuclein aggregation

Major question to be answered:   Which part of the α-synuclein sequence is essential for α-synuclein oligomerization and aggregation that are directly associated with PD?

Why is this important?   The identification of the α-synuclein target that contributes to its aggregation will pave the way for novel ways to inhibit α-synuclein aggregation and potentially treat PD.
One of the potential therapeutic strategies to combat PD is the effective inhibition of α-synuclein aggregation. Identifying the parts of α-synuclein that are essential for oligomerization and aggregation is an important part of preventing aggregation. We will use a biochemical approach in tandem with numerous in vitro and in vivo PD models to identify α-synuclein sequences and their structural features which mediate the formation of neurotoxic α-synuclein oligomers.

Huiliang Wang, PhD
University of Texas at Austin
Sono-optogenetic stimulation for Parkinson disease treatment in rats

Major question to be answered:  Can the technology of sono-optogenetics achieve long-lasting motor recovery in a rat model of PD?

Why is this important? This study is the first step in development of sono-optogenetics as a better treatment method (non-invasive, long-lasting effect) for PD as compared to current deep brain stimulation approaches.
Optogenetics is a technique that uses light to control cellular processes. Neurons can be genetically modified so that they express light-sensitive ion channels. The neurons are then exposed to light in specific spatial or temporal patterns to allow for manipulation of these ion channels, and therefore manipulation of electrical circuitry in the brain. In this work, a modified optogenetics technology in a rat model of PD called sono-optogenetics, will be applied. Nanoparticles (tiny particles that are between 1 and 500 nanometers in diameter) that emit light when they are stimulated by focused ultrasound will circulate in the blood stream. The light will then be used to control the neurons that contain the light-sensitive ion channels. The project will study whether controlling the neurons in this way achieves longer-lasting motor recovery in a rat model of PD than achieved using deep brain stimulation, without the need for electrode implantation.

Tips and Takeaways

• Every grant we fund has been reviewed by our Scientific Advisory Board. The grants listed above were selected with extreme care and determined to be the most meritorious.
• While some of the scientific terminology might be hard to follow, these research projects are incredibly exciting and have the potential to help make significant progress in the fight against Parkinson’s.
• All of the cutting-edge research described above is only possible due to the support and generosity of our donors. Click here to help us in this critical mission.
• We encourage you to learn more about all of the research APDA has fundedover the years.