Grants & Funding > American Parkinson Disease Research Grants 2013

American Parkinson Disease Association is using its 2013 distribution to fund:

The Role of Glucocerebrosidase and Chaperone-mediated Autophagy in Parkinson’s disease

Mobile Health Technology (MHT) to Promote Physical Activity in Persons with PD

LRRK2 in Pathological Synuclein Transmission

PROJECT TITLE:  The Role of Glucocerebrosidase and Chaperone-mediated Autophagy in Parkinson’s Disease
Investigators/Authors:  Sheng-Han Kuo, M.D., Columbia University
Objective:  In this proposal, we will investigate whether the disease-causing glucocerebrosidase (GBA) mutations can perturb a major pathway for a-synuclein  degradation, chaperone-mediated autophagy (CMA) and subsequently lead to a-synuclein accumulations and neurodegeneration, two hallmarks of Parkinson’s disease (PD) pathology.

Background:  GBA mutations are the most common genetic risk factors for PD and the majority of PD patient brains have a-synuclein aggregation, called Lewy bodies. How GBA mutation cause a-synuclein accumulation remains uncertain. We specifically investigate the effect of mutant GBAs on the a-synuclein degradation pathway, CMA.

Methods/Design:   We will introduce either wild type GBA or two disease-related mutant GBAs by lentivirus to the primary mouse dopaminergic neuronal cultures. We will assess whether expressing the exogenous mutant GBAs can interfere with 1) CMA activity assessed by a novel CMA reporter, 2) a-synuclein protein levels, and 3) neuronal death. We will examine whether toxic effects of GBA mutations act through a-synuclein by introducing mutant GBAs into primary dopaminergic neuronal cultures that do not have a-synuclein. If toxic effects of GBA mutations are mediated via a-synuclein, we can expect that genetic elimination of a-synuclein can rescue neuronal toxicity of mutant GBA. Finally, we will investigate the role of CMA in this pathway. We will delete the essential part of mutant GBAs that is required to interfere with CMA. We expect that this manipulation can eliminate the toxic effects of mutant GBAs on a-synuclein accumulation and neuronal death, highlighting the
importance of CMA. This study will comprehensively examine the relationship between GBA, CMA, and a-synuclein.

Relevance to Parkinson’s disease: We will investigate the mechanism behind the most common form of genetic PD with the GBA mutations and how these mutations can lead to the PD pathology, specifically focusing on CMA. The current research proposal will help us to have a better understanding of the PD disease mechanism and the intervention on CMA might be a promising strategy to treat PD. 

September 2014 Project Update:

We tested whether GBA (the most common gene associated with PD) mutation was neuronal toxic as the results of CMA (chaperone-mediated autophagy) blockade and impaired protein degradation in the cell.  Our findings suggest that neurotoxicity of GBA mutation was a-synuclein dependent.

In addition, with the aid of APDA funding, we have obtained the frozen brain samples (all anterior cingulate cortex, that are involved in Stage 5 of PD) from the New York Brain Bank.  The data we collected suggested that GBA mutation could cause DA neuronal toxicity and this process of a-synuclein dependent.  GBA also perturbs CMA machinery (underlines the pathogenesis of PD), particularly LAMP2A (single membrane protein) levels.  Further Studies will need to confirm that GBA mutation lead to a-synuclein accumulation, which could be due to the CMA blockade.  Interventions on the CMA steps can potentially provide a novel therapy for PD.

September 2015 Project Update:

We have made a significant progress since the last progress report. We studied the effects of glucocerebrosidase (GBA) mutation, the most common genetic mutation in PD, and depending on the ethnic background, approximately 7-20% of all PD patients carry genetic mutations in GBA. We are interested in looking a specific pathway of a-synuclein degradation, since a-synuclein aggregates are the pathological hallmarks of PD and insufficient a-synuclein degradation is central to the pathomechanism of PD. GBA resides in this particular organelle called lysosomes and the majority of a-synuclein is degraded by lysosomes. Therefore, our research goal is to see how GBA mutation could disturb lysosomal function leading to insufficient a-synuclein degradation.of GBA  made the mutant GBA proteins traffic to the outside rather than inside of the lysosomes and the mis-trafficking of mutant GBA causes lysosomal dysfunction and subsequently lead to a-synuclein accumulation. We also had a detailed mapping of mutant GBA protein to figure out which part of the protein is responsible for this pathological cellular process. We found mis-trafficked mutant GBA protein could bind hsc-70, a chaperone molecule, that’s critical to interfere with a-synuclein degradation. Thus, the interactions between hsc-70 protein and mutant GBA protein are critical for this toxic effects of mutant GBA. We have identified a very important step how most common genetic mutation in PD (i.e. GBA mutation) can cause PD pathology in patient brain (i.e.a-synuclein aggregates). Thus, our findings could serve as an important therapeutic target for PD patients with GBA mutations. In addition, decreased GBA activity has also been found in PD patients without GBA mutations. Therefore, our observation could be generalized to a broader PD population without GBA mutations, also.

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 PROJECT TITLE:  Mobile Health Technology (MHT) to Promote Physical Activity in Persons with PD

Investigators/Authors:  Terry Ellis, PhD PT, NCS; Nancy Latham, PhD, PT; Cathi Thomas, RN, MS, CNRN; Marie Saint-Hilaire, MD, FRCPC; Tami Rork DeAngelis, PT, DPT, GCS; Katy Hendron, PT, DPT, NCS.

Objectives:  1) To determine the efficacy of a MHT-mediated exercise program to improve physical activity six months after randomization in persons with PD compared to a controlled condition without MHT; 2) compare the percentage of days within that period that subjects and controls exceed the minimum threshold index indicating a sedentary lifestyle; 3) determine whether a MHT-mediate exercise program improves motor function, non-motor function, quality of life, exercise self-efficacy and outcome expectations in persons with PD compared to controls.

Background:  PD causes significant function decline resulting in greater disability, but can be improved through exercise. People with PD have long lifespans so exercise is essential in improving their function, and because indefinite PT is not realistic, interventions using MHT allow therapists to stay connected over time to meet patients’ changing needs. Innovative approaches using MHT may improve outcomes, however, the effectiveness of different approaches to improve function to reduce disability is unknown. The purpose of this study is to compare the effectiveness of two interventions to improve function and health-related quality of life in people with PD.

Methods/Design:   Fifty persons after a baseline assessment are randomly allocated into one of two home exercise conditions for six months with one in-person instructional session and a final assessment. One group receives a home exercise program in written format to continue independently. The other group has the exercise program delivered via videos on a computer table that allow the PT to remotely monitor progress and modify the program to meet changing needs. The long-term objective is to determine the most efficient and effective way to improve function. The primary outcome for the study is the change in physical activity level from the baseline to the six-month assessment measured by recording step counts across seven days before and seven days after the six-month intervention. Other outcomes include disease severity, quality of life, walking ability, balance, function related to non-motor symptoms and confidence in ability to exercise.

Relevance to Parkinson’s disease: The importance of physical activity for persons with Parkinson’s disease has been drastically undervalued. A sedentary lifestyle hastens disability. Exercise prescription is not part of the standard clinical management of persons with the disease. Effective strategies to increase physical activity are essential in reducing disability, improving physical function and enhancing quality of life. If this approach is successful, the standard clinical management of persons with PD could be impacted. This approach is easily accessible to most, generalizable to many, and conducive to widespread dissemination.

September 2014 Project Update:

We received a second year of funding which allowed us to increase the length of our intervention from six months to 1-year.  This is an important step and allows us to assess the effectiveness of using mobile health technology to help people with PD exercise over the long-term.  We have completed our study enrollment with 51 persons with PD currently participating in the study.  We expect to complete the final assessments in the spring of 2015 and submit manuscripts for publication in the fall of 2015.  These results will serve as the basis for further studies to be submitted to the Patient Centered Outcomes Research Institute (PCORI) and to the National Institutes of Health (NIH).

September 2015 Project Update:

  • Research team meetings were initiated during the summer of 2013 prior to the start of the funding period (September 2013). 
  • The study protocol was finalized, the staff was trained and equipment was ordered followed by submission of the IRB proposal in August of 2013.
  • We received IRB approval in October of 2013 at which time we initiated recruitment.
  • Enrollment was completed as of July 2014.  In total, 60 subjects were screened.
    • 44 subjects have completed the study
    • 7 subjects dropped out (4 controls – scheduling conflict; no longer interested in participating; knee pain with walking; shoulder pain; 3 from intervention – medical issues unrelated to PD,  decided not to continue after 6 months (2).
    • 9 subjects did not meet inclusion criteria (screen failures: 6 due to cognitive impairment; 1 due to disease severity > H&Y 3; 1 due to freezing of gait)
  •  In June 2014, our research grant application was funded for fiscal year 2014-15 which extended the current study from one year to two years.  This allows an increase in the intervention period from six months to one year.  This will allow us to assess the effectiveness of the mHealth technology mediated exercise program over the long-term (1 year).
  • Assessments conducted at baseline, 3-months, 6-months and 12-months have been completed.

Presentations / Grant Proposals:

  • An abstract was accepted to the IV Step Conference, a national physical therapy conference focused on application of novel models of care into neurological physical therapy practice.  This conference will be held in Columbus, Ohio in July of 2016.
  • An Educational Session entitled “Application of mobile health technology to facilitate long-term engagement in exercise in persons with Parkinson Disease” will be presented at the APTA MA Conference on November 14, 2015.  Based on our preliminary data at 6 months, an Investigator Initiated R01 grant proposal was submitted in response to PA-14-344 (Self Management for Health in Chronic Conditions) June 5, 2015.  This is currently under review.    

Next Steps:  

  • Complete data analysis and manuscript during the fall of 2015.
  • Submit a manuscript for publication during the fall of 2015.   Present study results at a national PT meeting (February 2016), the International congress of Parkinson Disease and Movement Disorders (Berlin, 2016) and the World Parkinson’s Congress (Portland, 2016).   
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 PROJECT TITLE:  LRRK2 in Pathological Synuclein Transmission 
Investigators/Authors:  Laura Volpicelli-Daley, PhD
Objective:  Lewy Bodies (LBs) and Lewy Neurites (LNs) are among the primary hallmarks of Parkinson’s disease. These are protein aggregates found in the cell bodies and axons of neurons which are mostly composed of the protein, a-synuclein (a-syn). At the University of Pennsylvania, a novel model was developed in which, for the first time, we can induce formation of LB and LN-like aggregates in neurons in culture. In this model, pathologic fibrils of a-syn are formed in a test tube and added directly to neurons in a culture dish. These “pre-formed” fibrils, lead to the recruitment of normal a-syn expressed in the neurons into abnormal aggregates. Over time, these aggregates lead to neuron death. This model allows us to understand how these abnormal aggregates form, their impact on neuron function and, ultimately, identify therapeutic targets to prevent their formation.

Background:  a-Syn and LRRK2 are 2 autosomal dominant causes of Parkinson’s disease (PD) and among the top genetic susceptibility loci identified in genome wide association studies. In addition, LRRK2 has recently emerged as a therapeutic target for PD and potent and specific inhibitors of LRRK2 have already been developed. The familial linked LRRK2-G2019S mutation increases the activity of the protein which has been associated with neuron death. We will determine if the LRRK2-G2019S mutant accelerates a-syn pathology and conversely, if LRRK2 inhibitors prevent the formation of abnormal LBs and LNs.

Methods/Design:   We will use antibodies that recognize the abnormal form of a-syn and imaging with a confocal microscope (a microscope that is able to filter out the out-of-focus light from above and below the point of focus in the object) to visualize its formation over time. Biochemical methods will be used to quantify conversion of a-syn from its normal, soluble form to an abnormal form that becomes insoluble in detergent as it is converted into LB- and LN- like aggregates. We will determine if specific inhibitors of LRRK2 activity will prevent this conversion of a-syn into its abnormal form. Neuron cultures from the transgenic mice expressing LRRK2-G2019S will be used to determine if this familial mutant causes a-syn aggregates to form faster, consequently accelerating cell death.

Relevance to Parkinson’s disease: These studies will begin to determine if LRRK2 inhibitors can prevent the formation of neuronal pathologic aggregates and enhance neuron survival reducing or eliminating the threat of cell death.

September 2014 Project Update:

We have preliminary findings that LRRK2G2019S mutations interact with pathologic a-syn and that LRRK2 inhibitors may play a role in this interaction. Recent emerging evidence indicates that abnormal forms of a-syn can spread to interconnected neurons within the brain in a predictable pattern, and cause neurodegeneration in a manner that recapitulates the progression of pathology found in Parkinson’s disease (PD) brains. We will determine the impact of mutant LRRK2 on the spread of a–syn.  These studies will help to determine a possible way of reducing or eliminating the threat of cell death.

September 2015 Project Update:

We have found in cell culture in vitro and in the rat brain in vivo, that expression of LRRK2G1019S mutations associated with Parkinson’s disease increase the abundance of alpha-synuclein inclusions relative to neurons expressing wild type LRRK2. In addition, we have also shown that selective, potent, LRRK2 inhibitors reduce inclusion formation in neurons with mutant LRRK2G2019S. Thus, LRRK2 inhibitors may be effective in delaying the spread of alpha-synuclein pathology throughout the brain.

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