Development of a novel cell model for LRRK2 Parkinson's Disease
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
Parkinson‘s disease (PD) is a very common and devastating neurological condition which leads to progressive difficulty with movement and memory. The disease is caused by certain nerve cells gradually dying in the brain. However, little is known about why this happens and currently there is no cure.
Rarely, certain genetic mutations can lead to PD being inherited in families. Understanding how these mutations cause disease in these families can help us to understand the more common form of PD in the general population.
We are investigating the most common form of inherited PD which occurs due to mutations in a gene called LRRK2. Our aim is to develop a novel model for PD using skin cells from PD patients who have these particular mutations. Using new techniques, we can convert these cells into the specific nerve cells that die in PD. By comparing these cells to equivalent cells from healthy individuals, we plan to find out precisely how LRRK2 mutations cause disease.
Our understanding of how LRRK2 causes PD will be harnessed to develop strategies to intervene in this process. This will ultimately enable us to develop treatments that halt the development and advancement of the common form of PD.
Rarely, certain genetic mutations can lead to PD being inherited in families. Understanding how these mutations cause disease in these families can help us to understand the more common form of PD in the general population.
We are investigating the most common form of inherited PD which occurs due to mutations in a gene called LRRK2. Our aim is to develop a novel model for PD using skin cells from PD patients who have these particular mutations. Using new techniques, we can convert these cells into the specific nerve cells that die in PD. By comparing these cells to equivalent cells from healthy individuals, we plan to find out precisely how LRRK2 mutations cause disease.
Our understanding of how LRRK2 causes PD will be harnessed to develop strategies to intervene in this process. This will ultimately enable us to develop treatments that halt the development and advancement of the common form of PD.
Technical Summary
Parkinson‘s disease (PD) is the most common neurodegenerative movement disorder. The pathology of progressive loss of dopaminergic neurons in the substantia nigra is well known, but the mechanisms by which this occurs are not understood. As a consequence, curative treatments for this disease currently do not exist.
Progress in our understanding of the pathological changes has been made by studying the rare inherited forms of the disease: these individual mutations can provide a foothold for understanding the pathogenesis of PD. However, it is not clear whether these inherited cases represent the same condition as sporadic PD.
We are investigating the most common form of inherited PD, caused by mutations in LRRK2 - which replicates the phenotype of sporadic PD very closely. Previous work has suggested that the kinase domain of LRRK2 plays a pivotal role, with some of its mutations being associated with increased kinase activity, whilst the toxicity of mutated LRRK2 is reduced when it is expressed on a kinase dead background. However, it is unclear whether this is the case with all disease-causing LRRK2 mutations, and progress is hampered because studies rely upon cell models derived from tumour cells or rodent neurons, which are very different to the cells that degenerate in PD. New model systems are required in order to take matters forward.
Our aim is to develop a novel cell model of LRRK2 PD using fibroblasts from PD patients with LRRK2 mutations, taken from skin tissue obtained by punch biopsy. Using new techniques, pioneered by Takahashi and Yamanaka at the University of Kyoto, these cells will be stimulated to enter a stem-cell-like state, after which they will be induced to form dopaminergic neurons, mimicking the cells that degenerate in PD.
Cells carrying LRRK2 mutations will be compared with equivalent cells from control subjects at both the fibroblast and dopaminergic neuron level in order to better understand how these mutations lead to neuronal death. Kinase behaviour and signal pathway activation will be areas of particular interest. We hope to harness this information to develop strategies to intervene in the pathogenetic pathway in order to develop treatments that could halt neurodegeneration in LRRK2 PD, and therefore ultimately treat the more common sporadic form of the disease.
Progress in our understanding of the pathological changes has been made by studying the rare inherited forms of the disease: these individual mutations can provide a foothold for understanding the pathogenesis of PD. However, it is not clear whether these inherited cases represent the same condition as sporadic PD.
We are investigating the most common form of inherited PD, caused by mutations in LRRK2 - which replicates the phenotype of sporadic PD very closely. Previous work has suggested that the kinase domain of LRRK2 plays a pivotal role, with some of its mutations being associated with increased kinase activity, whilst the toxicity of mutated LRRK2 is reduced when it is expressed on a kinase dead background. However, it is unclear whether this is the case with all disease-causing LRRK2 mutations, and progress is hampered because studies rely upon cell models derived from tumour cells or rodent neurons, which are very different to the cells that degenerate in PD. New model systems are required in order to take matters forward.
Our aim is to develop a novel cell model of LRRK2 PD using fibroblasts from PD patients with LRRK2 mutations, taken from skin tissue obtained by punch biopsy. Using new techniques, pioneered by Takahashi and Yamanaka at the University of Kyoto, these cells will be stimulated to enter a stem-cell-like state, after which they will be induced to form dopaminergic neurons, mimicking the cells that degenerate in PD.
Cells carrying LRRK2 mutations will be compared with equivalent cells from control subjects at both the fibroblast and dopaminergic neuron level in order to better understand how these mutations lead to neuronal death. Kinase behaviour and signal pathway activation will be areas of particular interest. We hope to harness this information to develop strategies to intervene in the pathogenetic pathway in order to develop treatments that could halt neurodegeneration in LRRK2 PD, and therefore ultimately treat the more common sporadic form of the disease.