Two MPAN grants worth $140,000 awarded to further disease insights
December 2022
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The NBIA Disorders Association, along with three sister organizations in Europe, have awarded two MPAN grants that will forward research priorities set during a workshop on Mitochondrial Membrane Protein-Associated Neurodegeneration.
Dr. Lena F. Burbulla of the Ludwig-Maximilian University in Munich, Germany, and Dr. Rajnish Bharadwaj of the University of Rochester Medical Center, Rochester, New Jersey, each received one-year research grants of $70,000 to study MPAN.
The funding was made possible through an international collaboration that also included the Associazione Italiana Sindromi Neurodegenerative da Accumulo di Ferro (AISNAF) in Italy, Hoffnungsbaum e.V. in Germany and Stichting Ijzersterk in The Netherlands.
In a 2021 workshop led by Dr. Francesca Sofia, founder and chief executive of Science Compass in Milan, Italy, researchers collaborated to collect data as well as assess strengths, challenges, and trends in MPAN research to establish a set of scientific priorities. For details, see page 8 of our December 2021 Newsletter.
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| Dr. Lena Burbulla of Ludwig-Maximilian University in Munich, Germany, receives a $70,000 research grant to study MPAN in December. |
Burbulla’s research involves human disease modelling by creating patient-derived cells to discover new underlying mechanisms driving pathology in MPAN. To do so her lab uses induced pluripotent stem cells (iPSCs) generated from skin cells from people affected with MPAN. Burbulla’s team will utilize these stem cells – that theoretically can be turned into any type of cell in the body – to generate dopaminergic nerve cells that are known to be affected in MPAN patient brains. Dopaminergic nerve cells produce the neurotransmitter dopamine, a chemical messenger involved in regulating body movements, memory, motivation, attention, learning and more.
Mutations in one specific gene, C19orf12, are the only known cause of MPAN. The function of the resulting protein C19orf12 remains largely unknown. Disease modelling approaches will help the researchers examine, in a patient-specific model, the C19orf12 protein function and, most importantly, how brain cells are impacted when this protein is impaired or lost. Burbulla and her team will investigate the effect of loss of C19orf12 function in mitochondrial health in these patient nerve cells. The mitochondria are the “powerhouses of the cell” producing about 90% of the energy cells need to survive. When mitochondria are damaged, disastrous consequences for the cell can occur, along with a toxic series of events that culminate in nerve cell death. Given that the C19orf12 protein is known to associate with mitochondria, its loss of function may affect mitochondria and have wide-ranging impacts on cell health and resilience.
The stem cell model will enable the researchers to compare the MPAN cells to healthy cells and better understand the protein’s role. They will also look beyond mitochondria for disease-associated pathology, probing for possible alterations in the processing of the neurotransmitter dopamine in these nerve cells, as well as a protein called alpha-synuclein, known to pathologically accumulate in MPAN patient brains.
Alpha-synuclein is found on the ends of nerve cells in the synaptic terminals — the area between neurons where the neurotransmitters are released to relay messages throughout the body. Abnormally shaped or overly abundant alpha-synuclein leads to aggregation, or clustering, of the proteins and inhibits normal neuron function.
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| Dr. Rajnish Bharadwaj of the University of Rochester Medical Center, in Rochester, New Jersey, receives a $70,000 grant to research MPAN in December. |
Baharadwaj’s research will focus on better understanding the proteins produced by the C19orf12 gene. His team will use fruit fly models that have been genetically engineered to lack the CG3740 and CG11671 genes, which correspond to the C19orf12 gene in humans.
Previous studies from other groups and his ongoing work have shown that the model flies have shorter life spans, deficits in movement and loss of neurons in the brain and retina. This suggests that the fruit flies will be a promising model to study NBIA.
The team’s studies also suggest the C19orf12 is a membrane contact site protein that may be involved in communication between organelles, specialized subunits within the cell, such as the endoplasmic reticulum and lipid droplets (fats). The endoplasmic reticulum’s role in the cell is to produce proteins, and it’s involved in the production and storage of lipids.
The team’s goal is to study how the C19orf12 protein is involved in lipid metabolism and mitochondrial function. Lipid metabolism is the process of production and degradation of lipids, or fats, in cells. The researchers want to uncover this role in the brain and other organs. Both lipid metabolism and mitochondrial function are implicated in other forms of NBIA as well.
Overall, the creation and study of these disease models and subsequent research will advance the understanding of MPAN and pave the way for developing treatments.
