Neuron: La Spada et al links Nna Proteins to mitochondrial dysfunction in neurodegenerative diseases

Dr. Albert La Spada

Animal models offer clues to similar neurodegenerative disorders in humans, such as Parkinson’s

June 24th Dr. Albert La Spada – Division Chief of Genetics in UC San Diego’s Department of Pediatrics and Cellular and Molecular Medicine, recently identified Nna proteins as key players in the dramatic loss of neurons in mice and fly models, a discovery that could help illuminate the role of mitochondrial dysfunction in human neurodegenerative disorders, such as Parkinson’s disease.

In collaboration with colleagues at UC San Diego and Rady Children’s Hospital, the University of Nottingham Medical School and the University of Washington Medical Center, Dr. La Spada found that the loss of Nna proteins caused by a defective Nna gene alters the biochemistry of energy flow within nerve cells, resulting in severe mitochondrial abnormalities that may be linked to massive cell death, leading to the rise of neurodegenerative disorders.

“In certain neurological diseases like Parkinson’s, it’s long been known that mitochondrial dysfunction is involved,” La Spada said. “Mitochondria are the power plants of cells. They control the biochemical pathways that generate most of a cell’s energy. We’ve shown that when Nna proteins aren’t working properly, there is much greater vulnerability for mitochondrial dysfunction.”

The research study involved two animal models: Purkinje cell degeneration (pcd) mice and Drosophila fruit flies. First discovered in 1976 at the Jackson Laboratory in Bar Harbor, Me., the mice display a novel, genetic neurological phenotype in which they suffer rapid, massive neuron loss. Although born with a normal complement of Purkinje cells – a class of neurons in the cerebellum that are involved in motor control – pcd mice almost immediately begin losing these cells. At three weeks old, so many Purkinje cells have died off that newly weaned mice move and walk awkwardly. By six weeks of age, they have lost more than 99 percent of their Purkinje cells and display severe gait ataxia, or grossly uncoordinated movement.

In addition, pcd mice suffer a sharp, progressive decline in photoreceptor cells. By 10 ½ months of age, most of the photoreceptor cells on the outer nuclear layer of their retinas have died, rendering the mice blind.

In the fly studies, La Spada and colleagues found that loss of analogous Nna proteins resulted in similar consequences. There was increased larval lethality, with survivors displaying phenotypes that mirrored the disorders of pcd mice.

The findings are important, said La Spada, because the Nna gene is highly conserved and can be found in multiple species, including humans. The striking similarities among mice and flies should help researchers better understand the role of Nna proteins in humans – and what happens when the human version of the Nna gene is defective.

“We still have much to learn, such as what the proteins are using for substrates and how their enzyme activity is involved in the biochemistry of mitochondria.   We have also discovered that Nna proteins may be regulating the turnover of mitochondria, but we don’t yet know if mitochondrial turnover causes the mitochondrial defect or if it is defective mitochondrial function that causes accelerated mitochondrial turnover,” said La Spada.

“It’s still a chicken-or-egg sort of question,” albeit one that might ultimately point the way to new therapeutic approaches for disorders like Parkinson’s, a currently incurable disease that afflicts approximately 1.5 million Americans, with an estimated 50,000 new cases diagnosed annually.

Co-authors of the paper were Lisa Chakrabarti of the School of Biomedical Sciences at the University of Nottingham Medical School; Rabaab Zahra, Parsa Kazemi-Esfarjani, Amanda G. Mason, Janice W. Kansy and Craig L. Bennett, all in the Department of Pediatrics at the University of California, San Diego-Rady Children’s Hospital; Stephen M. Jackson, Bryce L. Sopher and Jeremiah Eng of the Department of Laboratory Medicine at the University of Washington Medical Center; Thomas Toneff and Vivian Hook of the Skaggs School of Pharmacy and Pharmaceutical Sciences, UC San Diego; Soyoung Ryu, Scott Shaffer and David R. Goodlett of the Department of Medicinal Chemistry at the University of Washington Medical Center; Gennifer Merrihew, Michael J. MacCoss and Leo J. Pallanck of the Department of Genome Sciences, University of Washington Medical Center;  and Anne Murphy, Department of Pharmacology, UC San Diego.

Article Originally Written by Media Contact, Scott LaFee, 619-543-5232,

Modified by: Shivani Singh, Sr. Writer, Department of Pediatrics

SCIENTIFIC CONTACT: Dr. Albert La Spada, Division Chief of Genetics, Department of Pediatrics, Professor of Pediatrics and Cellular and Molecular Medicine, and Assistant Director for the Institute of Genomic Medicine,