Common molecular mechanisms in neurodegenerative diseases using patient based iPSC neurons

Common molecular mechanisms in neurodegenerative diseases using patient based iPSC neurons

Funding Type: 
Basic Biology IV
Grant Number: 
RB4-06079
Award Value: 
$1,506,420
Disease Focus: 
Huntington's Disease
Neurological Disorders
Parkinson's Disease
Stem Cell Use: 
iPS Cell
Cell Line Generation: 
iPS Cell
Status: 
Active
Public Abstract: 
A major medical problem in CA is the growing population of individuals with neurodegenerative diseases, including Parkinson’s (PD) and Huntington’s (HD) disease. These diseases affect millions of people, sometimes during the prime of their lives, and lead to total incapacitation and ultimately death. No treatment blocks the progression of neurodegeneration. We propose to conduct fundamental studies to understand the basic common disease mechanisms of neurodegenerative disorders to begin to develop effective treatments for these diseases. Our work will target human stem cells made from cells from patients with HD and PD that are developed into the very cells that degenerate in these diseases, striatal neurons and dopamine neurons, respectively. We will use a highly integrated approach with innovative molecular analysis of gene networks that change the states of proteins in these diseases and state-of-the-art imaging technology to visualize living neurons in a culture dish to assess cause and effect relationships between biochemical changes in the cells and their gradual death. Importantly, we will test whether drugs effective in animal model systems are also effective in blocking the disease mechanisms in the human HD and PD neurons. These human preclinical studies could rapidly lead to clinical testing, since some of the drugs have already been examined extensively in humans in the past for treating other disorders and are safe.
Statement of Benefit to California: 
Neurodegenerative diseases, such as Parkinson’s (PD) and Huntington’s disease (HD), are devastating to patients and families and place a major financial burden on California. No treatments effectively block progression of any neurodegenerative disease. A forward-thinking team effort will allow highly experienced investigators in neurodegenerative disease and stem cell research to investigate common basic mechanisms that cause these diseases. Most important is the translational impact of our studies. We will use neurons and astrocytes derived from patient induced pluripotent stem cells to identify novel targets and discover disease-modifying drugs to block the degenerative process. These can be quickly transitioned to testing in preclinical and clinical trials to treat HD and other neurodegenerative diseases. We are building on an existing strong team of California-based investigators to complete the studies. Future benefits to California citizens include: 1) discovery and development of new HD treatments with application to other diseases, such as PD, that affect thousands of Californians, 2) transfer of new technologies and intellectual property to the public realm with resulting IP revenues to the state with possible creation of new biotechnology spin-off companies, and 3) reductions in extensive care-giving and medical costs. We anticipate the return to the State in terms of revenue, health benefits for its Citizens and job creation will be significant.
Progress Report: 

Year 1

The goal of our study is to identify common mechanisms that cause the degeneration of neurons and lead to most neurodegenerative disorders. Our work focuses on the protein homeostasis pathways that are disrupted in many forms of neurodegeneration, including Huntington’s disease (HD) and Parkinson’s disease (PD). In this first reporting period we have made great progress in developing novel methods to probe the autophagy pathway in single cells. This pathway is involved in the turnover of misfolded proteins and dysfunction organelles. Using our novel autophagy assays, we have preliminary data that indicate that the autophagy pathway in neurons from HD patients is modulated compared to healthy controls. We have also begun validating small molecules that activate the autophagy pathway and we are now moving these inducers into human neurons from HD patients to see if they reduce toxicity or other disease related phenotypes. Using pathway analysis we have also identified specific genes within the proteostasis network that are modulated in HD. We are now testing whether modulating these genes in human neurons from HD patients can lead to a reduction in neurodegeneration. In the final part of this study we are investigating whether neurodegenerative diseases, such as HD and PD, share changes in similar genes or pathways, specifically those involved in protein homeostasis. We have now established a human neuron model for PD and have used it to identify potential targets that modulate the disease phenotype via changes in proteostasis. Using the assays, autophagy drugs and pathway analysis described above, we hope to identify overlapping targets that could potentially rescue disease associated phenotypes in both HD and PD.

© 2013 California Institute for Regenerative Medicine