Calcium homeostasis in Parkinson’s disease: Letm1 as a therapeutic target
University of Ottawa
Parkinson’s disease (PD) is a progressive, neurodegenerative disorder that predominantly affects the aging population. Although its causes remain unknown, ~10% of PD cases are linked to genetic mutations. One of these genes, Pink1, is believed to play a role in the mitochondria of our cells. Mitochondria are crucial organelles that control our metabolism, produce energy and balance calcium levels, which control the fate of our cells. Their function is critical in neurons, which constantly have high energy demands and are very sensitive to stress. However, exactly how mutations in Pink1 cause increased stress and neuronal death remains unknown. We have identified a novel target of Pink1 – the Letm1 protein. Letm1 can directly regulate how well our mitochondria can buffer calcium to maintain cellular levels in a healthy range. We have evidence that healthy Pink1 can activate Letm1, whereas when Pink1 is absent, the Letm1 that is detected is not activated. Using mice and rats lacking Pink1, compared to those with healthy Pink1, we are currently confirming that Pink1 has the ability to activate Letm1, which then controls its capacity to buffer calcium levels. Calcium imbalance leads to increased stress and could be the cause of cell death in PD.
Relevance to the acceleration of therapeutics for neurodegenerative diseases of aging
Defining the role of Pink1 has high implications for the understanding of genetics, and more specifically, the contributions of mitochondrial dysfunction and calcium impairments to PD. This is critical since determining that these disruptions are in fact causative factors has been speculated, but never established. The ability to validate the Pink1-Letm1 and/or the mitochondrial-calcium pathway will provide the field with a mechanism and potential target proteins for the testing and development of focused therapeutic strategies. This has a breath of applications, as many neurodegenerative diseases may share mitochondrial and calcium dysfunction as common characteristics.
Through these studies we hope to establish a direct link between the following key players: Pink1, Letm1, mitochondria and calcium dysregulation, leading to neurodegeneration. We will use the results to assess and validate our findings in genetic animal models of PD. We can then screen through candidate compounds that act on these targets to halt neurodegeneration. This will help narrow the focus of therapeutic designs and provide insight into disease origins and progression. Validating these targets will help attract research funding to advance the project and to encourage the recruitment of industry partners for the development/testing of clinical therapeutics.
A genetic mutation in the PTEN-induced putative kinase 1 (PINK1) gene confers a risk for development of Parkinson’s disease (PD) earlier than usual, at ages younger than 45. By contrast, the most common, non-familial forms of PD develop at about age 65. Our project is part of our effort to elucidate the normal functions of this gene in neurons.
We have found that PINK1 can modify another protein, LETM1, and facilitate calcium transport in mitochondria, the cell’s power plant. We also revealed that PINK1 mutations found in patients and or genetic loss of PINK1 results in dysfunction of LETM1 and mitochondrial calcium regulation. These events contribute to neurodegeneration in models of Parkinson’s disease. These finding demonstrate a potential biological target for therapeutic development. To substantiate this claim, we are currently studying the usage of calcium channel inhibitors to ameliorate disease progression in both familial or non-familial PD.