"[This] is an opportunity to test potential disease-modifying therapies."
Kateri Spinelli, Ph.D.
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2015 Investigator-Initiated Projects
Among PDF's research awards in 2015 are several novel investigator-initiated research projects. Abstracts of these projects appear below.
[+] Novel Insights into the Properties and Fate of Naturally Secreted Alpha-synuclein
Georgia Sotiropoulou, Ph.D., University of Patras
Scientists know that a protein called alpha-synuclein plays an important role in the death of certain brain cells, and that this cell death leads to Parkinson’s disease. It is also well known that alpha-synuclein forms toxic clumps inside of certain brain cells. But alpha-synuclein is also found outside of cells. One theory holds that the risk of PD increases when there is too much alpha-synuclein circulating outside of cells. This research project focuses on an enzyme, kallikrein-related peptidase 6 (KLK6), which may help break down and clear excess alpha-synuclein. We seek to understand, step-by-step, how levels of alpha-synuclein outside of cells are regulated. We are also looking for links between these levels and the development of PD. If the enzyme KLK6 is found to play a role in regulating alpha-synuclein levels, it provides a clue for developing new drugs. For example, it would demonstrate that drugs that increase the activity of KLK6 might have potential as PD therapies.
[+] Striatal CaV1.3 Calcium Channel Silencing as a Neuroprotective Target for Levodopa-induced Dyskinesias
Kathy Steece-Collier, Ph.D., and Frederic P. Manfredsson, Ph.D., Michigan State Universit
Levodopa is the gold-standard therapy for Parkinson’s disease. But after taking levodopa for several years most people develop dyskinesias – involuntary movements that are a side effect of the medication. Research has shown that when cellular calcium channels (the gateways that allow calcium into cells) are disrupted, the disruption plays a role in dyskinesias. In particular, one channel called CaV1.3 is implicated. Drugs already on the market for high blood pressure, called calcium channel blockers, are being investigated to treat dyskinesias. But they are not specific to CaV1.3, and thus only partially effective. This research, carried out in rats, investigates whether selectively blocking CaV1.3 might better protect against dyskinesias, and whether it can reverse dyskinesias after they have developed. The results will inform the development of calcium blocking therapies targeted at levodopa-induced dyskinesias.
[+] Neuroprotection by XPro1595 in a Chronic MPTP Monkey Model of Parkinson’s
Malú Tansey, Ph.D., and Yoland Smith, Ph.D., Emory University
Brain scans show that people with PD have more inflammation (the body’s response to injury or infection) in their brains than is normal. And studies suggest that drugs to treat inflammation may lower PD risk. We have already shown, in research on rodents with PD-like symptoms, that a new anti-inflammatory drug called XPro1595 penetrates into the brain and lessens and slows brain cell degeneration. Our new study will test the drug in monkeys that have been given MPTP, a substance that kills dopamine neurons and results in PD movement symptoms. If it is effective, XPro1595 will block or reduce the effects of the MPTP. This is an important step in moving this drug toward clinical trials in humans.
[+] Dysfunctional Signalling Mechanism of Neurotransmission in Parkinson’s Disease
Zhenyu Yue, Ph.D., Icahn School of Medicine at Mount Sinai
The neurons affected by PD use a chemical messenger called dopamine to help tell the body to move. Understanding how dopamine communicates is vital to developing new therapies for Parkinson’s disease. We recently identified a mutation in a gene that causes early-onset PD, which may help us to understand dopamine communication. This gene in which we found the mutation is responsible for a protein known as synaptojanin 1 (synj1), which plays a role in the transmission of dopamine from cell to cell. Our study uses novel laboratory methods to investigate the normal role of synj1 and what goes awry when it is mutated. In addition, we will study how synj1 interacts with another PD-causing gene, called LRRK2. A mutation in LRRK2 results in decreased dopamine transmission, which we think may because synj1 is impaired. Knowledge of how synaptojanin 1 mutations may cause PD could provide new targets for therapeutic intervention in PD.
[+] Alpha Synuclein Aggregation Causes Toxicity by Decreasing Functional Forms of the Protein
Matthew Benskey, Ph.D., mentor: Fredric P. Manfredsson, Ph.D., Michigan State University
Dopamine neurons, the brain cells that die in Parkinson’s disease (PD), are found to contain clumps of a protein called alpha-synuclein. These protein clumps are the telltale marker of PD – the evidence of the disease. However, no one has yet to demonstrate that the clumps themselves are responsible for the death of brain cells. As alpha-synuclein has an important physiological function, I propose that neurons are dying because these clumps sop up normal alpha-synuclein like a sponge. That is, cells are dying not because alpha-synuclein clumps are toxic but because the clumps are absorbing all the freely available protein, keeping the normal alpha-synuclein from doing its job. I will test this idea by creating cells that will both make alpha-synuclein that forms clumps and a form of the protein that is resistant to clumping and is able to continue to do its work in the cells. Knowing whether alpha-synuclein clumps are directly toxic or kill cells by depleting them of normal alpha-synuclein could lead to research on potential therapies to preserve normal alpha-synuclein function.
[+] Functional Analysis of Dopamine-dependent Circuits Activity in Parkinson’s Disease
Nan Li, Ph.D., mentor: Alan Jasanoff, Ph.D., Massachusetts Institute of Technology
A tiny part of the brain called the substantia nigra is densely packed with cells that produce the chemical messenger dopamine. When these neurons die in Parkinson’s disease, the dopamine is lost. Thus, much research has focused on how dopamine released from these dying cells relates to Parkinson’s disease in that part of the brain. However, other brain cells make and release dopamine throughout other parts of the brain. This study uses cutting-edge imaging techniques to visualize the effects of dopamine release, in three dimensions and in near real-time, both in the region of the substantia nigra and across the whole brain. The research will be carried out in normal healthy rodents and rodents engineered to have PD-like movement difficulties. Seeing these broad dopamine activity patterns will lead to a better understanding of what happens in the brain with different PD symptoms, and further our understanding of dopamine’s role in PD.
[+] Mechanisms for the Modulation of Striatonigral and Striatopallidal Neuron Activity by Phosphodiesterase 10A Inhibition in L- DOPA-induced Dyskinesia
Fernando Padovan Neto, Ph.D., mentor: Anthony R. West, Ph.D., Rosalind Franklin University
Levodopa is the gold standard medication for Parkinson’s disease. Yet, after taking this drug for several years, most people develop involuntary movements called dyskinesias. Many people with PD are eager to find solutions to control these movements. Levodopa works by increasing brain levels of the chemical messenger dopamine , and its dopamine message is received by cells (receptors) located in the brain’s striatum. In earlier research with animal models of PD, our team has shown that a molecule called TP10 was able to changes the response of dopamine receptors in the striatum and, as a result improved dyskinesias (without changing the levodopa’s effectiveness). Our new studies use electrophysiological methods to examine in more detail how specific dopamine receptors, known as D1 and D2, change in response to TP10. In particular, we will investigate the effects of TP10 on dyskinesias when one or the other of these receptors is blocked. The results will advance the development of new treatment options for controlling dyskinesias.
[+] In Vivo Modulation of Alpha-Synuclein Phosphorylation: Tracking Aggregates in the Living Mouse Brain
Kateri Spinelli, Ph.D., mentor: Vivek Unni, M.D., Ph.D., Oregon Health & Science University
A protein called alpha-synuclein builds up and forms toxic clumps inside the dopamine neurons of people with Parkinson’s disease. The alpha-synuclein molecules that make up these clumps have undergone a chemical change called phosphorylation. However, we do not yet know if phosphorylation causes clumps to form or does the opposite, causes them to disintegrate. We are trying to learn more. By tagging alpha-synuclein with a fluorescent dye and using specialized imaging techniques, we can observe clump formation and disintegration in the brains of living mice. This study will determine if manipulating the phosphorylation process, using drugs that affect the cell’s built-in chemical pathways, leads to the build up or disintegration of alpha-synuclein clumps. If these approaches to changing alpha-synuclein’s ability to clump are effective in mice, we could potentially design therapies to alter the same molecular pathways in people with Parkinson’s disease.
[+] Deciphering the Mechanism of Action of Parkin Using a Structure-Based FRET-Reporter System
Matthew Tang, Ph.D., mentor: Edward Fon, M.D., Montreal Neurological Institute, McGill University
Parkin is a protein that normally helps to protect neurons. However, when mutated, parkin causes rare, inherited forms of Parkinson’s disease. In earlier studies we determined the 3-D (three-dimensional) structure of parkin at the atomic level. We also found that parkin needs to be “turned-on” in order to do its work – and when turned on it change shapes to reveal an active site that is normally shielded. Using a system we developed – fluorescent probes in live cells – we can detect the structural changes that must occur to “turn on” parkin. We will use this system to identify proteins or other molecules that bind to parkin, and to investigate how they activate parkin. This will help us understand why mutated parkin fails to “turn on” in PD. Ultimately, these studies will help us discover parkin activators that might have potential as PD therapies.
[+] Novel Deep Brain Stimulation Paradigms on Treating Parkinsonian Non-human Primates and the Underlying Physiological Plasticity
Jing Wang, Ph.D., mentor: Jerrold Vitek, M.D., Ph.D., University of Minnesota
Deep brain stimulation, a standard therapy for Parkinson’s disease, delivers electrical impulses to the brain through permanently implanted electrodes. Researchers continue to seek ways to improve DBS and reduce its side effects – in part by studying how its electrical impulses affect the brain. Current DBS devices typically fire their electrical impulses at a steady rate around 130 times a second. Scientists believe this DBS approach works by counteracting pattern of brain activity (neural synchronization) in which neurons in the brain fire at the same time. This synchronized activity is found to contribute to PD symptoms. We have tested a new way of delivering DBS to better counteract this synchronization that is called coordinated reset (CR). Using monkeys with PD-like symptoms as research subjects, we found that CR DBS improved the PD symptom of rigidity, with effects lasting several weeks after stopping the DBS treatment. Our new research will further investigate the effectiveness of CR compared to traditional DBS with respect to many PD motor symptoms, and examine the associated physiological changes in brain circuitry. Our goal is a better understanding of CR’s effects and its potential as a PD therapy.
[+] Input- and Cell-type Specific Rewiring of Subcellular Connectivity in the Striatum in Parkinsonian Mice
Yu-Wei Wu, Ph.D., mentor: Jun Ding, Ph.D., Stanford University School of Medicine
To control the body’s movement, cells in different parts of the brain communicate with each other using both electrical and chemical signals. A “circuit diagram” of this activity would show that signals from three areas of the brain – the cortex, the thalamus, and the basal ganglia – converge in an area called the striatum. There, cells called spiny projection neurons somehow integrate this information and translate it into motor control. This study will map the details of this process at the level of individual cells in the brains of healthy mice and mice with PD-like symptoms. Using cutting edge electrophysiological techniques, including optogenetics, we can activate specific cells that provide input to the striatum, and read out the results of this stimulation. Our goal is to define the role of spiny projection neurons in the brain circuitry that controls voluntary movement, and how this changes in PD, and ultimately, to develop better treatments for PD.
[+] Phosphorylated Alpha-synuclein Peptides as Biomarkers of Parkinson’s Disease
Li Yang, Ph.D., mentor: Jing Zhang, M.D., Ph.D., University of Washington
There is currently no biomarker – a blood test or scan, for example – to definitively diagnose Parkinson’s disease. However there is the possibility of finding one in alpha-synuclein, the protein that forms potentially toxic clumps in brain cells in PD. Alpha-synuclein is also found in the in the cerebrospinal fluid (CSF) that bathes the brain and spinal cord and since CSF can be easily collected and tested, this has great potential as a PD biomarker. Furthermore, people with PD have overall lower levels of alpha-synuclein in their CSF than healthy people. One difficulty, however, is that alpha-synuclein can take several different forms, and the most commonly used methods for measuring alpha-synuclein in CSF do not detect all of them. We propose using an analytical chemistry measurement called mass spectrometry to identify all the different forms of alpha-synuclein, quantify them, and compare levels in people with PD with levels in healthy people. Ultimately, this research will identify potential biomarkers that could complement a physician’s observations in order to accurately diagnose PD.