This grant builds upon the research from a prior grant: Targeting the Unfolded Protein Response (UPR) Transcription Factor XBP-1 to Treat Parkinson's Disease
Objective/Rationale:
Our general aim is to investigate the role of a specific component of a cellular stress response, known as the Unfolded Protein Response, in the development of Parkinson's disease. We intend to define the possible therapeutic benefits of alleviating cellular stress using gene therapy strategies in a genetic model of the disease.
Project Description:
Parkinson's disease (PD) is the second most common neurodegenerative disease, characterized by impairment of motor control as a result from extensive neuron death. The primary mechanism responsible for the progressive neuronal loss in PD remains unknown. Clues have been obtained from families who have a genetic form of PD that is accompanied by a mutation in an important protein called alpha-synuclein. It has been suggested that perturbation in the function of a subcellular organelle called the endoplasmic reticulum (ER) may determine the pathological effects of alpha-synuclein and other genetic forms of PD. In this target validation project we aim to define the direct contribution of this stress pathway to PD using a pre-clinical model of familial forms of PD. By employing a gene therapy strategy to manipulate the levels of an essential factor of ER stress responses (termed XBP-1), we intend to assess the possible therapeutic benefits of targeting the pathway in PD. This work will help validating a novel therapeutic target, in addition to foster developing an experimental therapy to treat this important disease
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
We plan to define for the first time the actual role of the main cellular pathway against protein misfolding, known as the Unfolded Protein Response (UPR), in the development of PD. This research aims to determine whether or not the UPR is a valid target to design therapeutic strategies to treat PD patients. To pursue this aim we will test the efficacy of using the injection of Adeno-Associated Viruses (AAVs) to deliver the therapeutic gene, a technology that is currently in eight different clinical trials of PD patients.