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Funded Studies

The Role of the Unfolded Protein Response (UPR) in Parkinson's Disease

Our general objective is to investigate the role of the cellular stress responses linked to organelle damage such as the Unfolded Protein Response in the development of Parkinson's disease. In the long term, we also intend to define the possible therapeutic benefits of alleviating cellular stress using pharmacological approaches in a disease context.
Project Description:
PD is the second most common chronic, progressive 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. In this project we aim to characterize in detail the contribution of this stress pathway to PD using cellular and animal models of genetic and sporadic forms of the PD. By employing animals deficient in an essential factor of ER stress responses we intend to asses the possible therapeutic benefits of targeting the pathway in PD. This work will increase our understanding of the molecular bases of PD and may lead to the design of novel therapeutic strategies 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.
Anticipated Outcome:
This research grant aims to perform a systematic study to determine the susceptibility of UPR-deficient mice to develop hereditary and sporadic Parkinson's disease.

Final Outcome

Working in models lacking the protein known as X-Box binding protein-1 (XBP-1), Dr. Hetz and colleagues found that the models were protected against neurotoxicity. However, the models were more susceptible to neurotoxicity if crossbred with models overexpressing alpha-synuclein. He is currently carrying out additional experiments to clarify these differential effects.


  • Claudio Hetz Flores, PhD

    Santiago Chile

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