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Patient-specific iPS cell-derived Neurons and Disease-associated LRRK2 Mutations for Parkinson's Disease Research

Several underlying genetic risk factors are now established for Parkinson’s disease (PD). Mutations in LRRK2 are the most common genetic cause of the selective neurodegeneration in PD. However, the mechanisms linking the specific LRRK2 mutations with the disease process are poorly understood, which limits the development of therapeutic interventions. New human cell assays that model the disease with an authentic genetic background are required to accelerate PD research. This project and associated national consortium will develop such a new tool for the scientific community.

Project Description
In this project and as part of a national collaborative and interdisciplinary consortium, now including MJFF, we will use induced pluripotent stem (iPS) cell technology to generate defined types of patient-specific neurons with known mutations in PD genes. Several PD-associated LRRK2 mutations will be the focus of our cellular reprogramming and differentiation experiments, including a heterozygous mutation in the GTPase domain (R1441C) and hetero- and homozygous mutations in the kinase domain (G2019S). Fibroblast lines from age- and gender matched healthy subjects will be reprogrammed as controls. From each individual’s fibroblast line, 2-3 fully characterized, factor-free iPS cell lines will be generated. The iPS cell lines will be differentiated using our protocol into a defined population of neurons that includes a practical yield of the vulnerable ventral midbrain type of human dopaminergic neuron for research tool characterization.

Relevance to Diagnosis/Treatment of Parkinson’s Disease:  
By characterizing several iPS cell lines with known PARK mutations, especially LRRK2 mutation-associated disease phenotypes with iPS cell-derived neurons, we can gain new insights into the pathophysiology and perhaps even preSymptoms & Side Effects phases of neuronal dysfunction that are the critical targets for early diagnosis and potential neuroprotective interventions. Furthermore, the discovery of in vitro cell based PD-associated phenotypes can establish tools and a platform for high-throughput drug discovery.

Anticipated Outcome
By quickly providing a national resource for iPS cell lines relevant to PD that will be characterized in a meaningful way by the assembled collaborators, and made available as useful reagents to the large community of present and future PD researchers, this project is well positioned to accelerate clinically-oriented research, in particular with a priority and relevance to LRRK2 mutations in PD.


  • Ole Isacson, MD, PhD

    Boston, MA United States

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