Parkinson’s Awareness Week starts on World Parkinson’s Day – April 11th and ends on Saturday 17th. Its purpose is to raise public awareness and promote knowledge about the disorder affecting millions of people worldwide, and to raise funds to support research and people affected. Unfortunately currently, there is no cure for Parkinson’s disease (PD) or a method at least to delay its progress, and only symptomatic treatments are available. More research is needed to develop better therapies and efficient drugs.
PD is a common neurodegenerative disorder resulting in both motor and non-motor symptoms. About half of people with PD suffer from anxiety or depression, which worsen other symptoms such as stiffness, tremor, and sleep problems. The pathological hallmark of PD is loss of dopaminergic neurons in the substantia nigra pars compacta. The etiology of PD involves multiple factors, including genetic and environmental ones. Only about 5% of patients have the inherited form of PD due to mutations in genes such as α-SNCA, ATP13A2, DJ-1, LRRK2, Parkin or PINK1. In different PD cases there is an apparent intracellular calcium ions dysregulation, e.g. loss of function of PINK1 gene leads to calcium ions mishandling. PINK1 is a serine-threonine kinase and is an activator of Parkin-mediated ubiquitylation. Together they work as a quality control to maintain a healthy pool of mitochondria. Mitochondria are vital for cellular physiology, e.g. for ATP generation, and mitochondrial calcium ion is a key player in cell functioning and survival. Aberration in mitochondrial calcium ions homeostasis plays, among several other factors, an important role for the neuronal loss in PD. Although the mutations that cause these conditions are known, it is not clear how they lead to the loss of dopaminergic neurons.
The team of the Laboratory of Neurodegeneration at the International Institute of Molecular and Cellular Biology in Warsaw develops and studies zebrafish models of PD to detect molecular, cellular and systemic effects of mutations in PD genes. We showed that that inhibiting mitochondrial calcium uniporter (Mcu), the main calcium ions entry pathway into mitochondria, using antisense morpholinos, rescues dopaminergic neurons in pink1−/− zebrafish model of PD. This suggests that mitochondrial calcium ions overload coupled with depolarization of mitochondrial membrane potential that lead to mitochondrial dysfunction in the pink1−/− fish is responsible for the loss of dopaminergic neurons. We also generated a knockout mcu−/− zebrafish line using the CRISPR/Cas9 system and showed impaired mitochondrial calcium ions influx. We found that dopaminergic neurons were rescued in fish mcu−/− and pink1−/− double fish knockouts. Moreover, in mcu−/− zebrafish treated with a drug known to damage dopaminergic neurons, called MPTP, these neurons were not affected. Thus, inactivation of Mcu is protective in both genetic (pink1−/−) and environmental (MPTP) models of PD indicating importance of mitochondrial calcium ions overload in inducing PD pathology. These data reveal that regulating Mcu function could be an effective therapeutic target in PD pathology: see figure below and our recent review (Cell Calcium 89, 2020, 102216).
