Could infectious agents hold the key to treating neurodegenerative disease? The idea may not be as crazy as it sounds. Some neuropathogens have evolved ways to turn off cell death mechanisms to keep their hosts alive. The same approach might rescue sick neurons in diseased brains, according to a paper in the 21 October Nature Communications. Researchers led by Daniel Gonzalez-Dunia at INSERM in Toulouse, France, reported that the anonymous-sounding protein X from the Borna disease virus protected axons and neurons from degeneration in a mouse model of Parkinson’s disease. Protein X, as well as a peptide derived from it, bolstered mitochondrial function in the stressed cells. The strategy might work for other disorders characterized by mitochondrial dysfunction, such as amyotrophic lateral sclerosis (ALS) and Alzheimer’s disease, suggest the researchers. “This peptide serves as a proof of concept that opens the way for designing new neuroprotective drugs,” Gonzalez-Dunia told Alzforum.
“I found the paper very intriguing,” said Brian Balin at the Philadelphia College of Osteopathic Medicine, Pennsylvania. “It offers a lead into how you could combat neurodegeneration.” Balin, who was not involved in the research, has studied links between infectious agents and dementia.
Borna disease virus (BDV) is an RNA virus that occurs throughout the world and mostly infects animals, particularly horses and sheep. In these species, the disease hampers movement, behavior, and learning, and often leads to death. People can harbor the virus as well, but researchers disagree on whether the infection leads to any visible symptoms. Some studies have linked BDV to neuropsychiatric disorders, but others refute this connection (see, e.g., Miranda et al., 2006; Hornig et al., 2012). The virus integrates into neuronal DNA, where it persists for years. In cultured glial cells, the virus’ protein X clings to mitochondria and prevents apoptosis (see Poenisch et al., 2009; Li et al., 2013).
Gonzalez-Dunia and colleagues wondered if BDV could protect neurons from nonviral stressors as well. First author Marion Szelechowski infected cultured primary neurons with BDV, then applied the toxin rotenone to their axons. Rotenone disrupts the mitochondrial electron transport chain, and in control cultures causes axons to gradually die back to the cell body. However, BDV-infected axons remained intact (see image above). Since previous work had flagged protein X as anti-apoptotic, the authors next applied a recombinant version to fresh cultures, and found that the protein alone protected axons from rotenone as well as did BDV infection.
Because rotenone causes a Parkinson-like disorder in rodents, the researchers wanted to see if protein X also protected neurons in a mouse model of PD. They injected a lentivirus expressing the protein into the substantia nigra of mice two weeks prior to treating them with the neurotoxin MPTP, which, like rotenone, targets mitochondria and kills dopaminergic neurons. As a control, they used a mutated version of the protein that lacked a mitochondrial localization sequence. Three weeks after MPTP administration, control animals had lost about a third of their dopamine neurons, while those receiving protein X maintained them.
While the findings suggested protein X might have therapeutic potential, the researchers felt the viral delivery method was cumbersome. The authors examined various domains of the protein to see if they could find a fragment that retained activity and could be more easily administered. They found that the C-terminal third, with a mitochondrial localization tag added, provided as much protection as full protein X. This small peptide, which they called PX3, could be administered intranasally, achieving high levels in the striatum and distributing throughout the brain and spinal cord, as well as in some peripheral organs. Mice who sniffed up the spray a day before MPTP injection retained 40 percent more dopamine neurons than control animals.
How do protein X and PX3 work? Mitochondria in treated cells grew up to four times longer than those in control neurons. This probably results from fusion of mitochondria, and represents a response to cellular stress, Gonzalez-Dunia told Alzforum. The massive mitochondria produce more energy and may dilute apoptotic signals, allowing cells to survive, he suggested.
Normally, dynamin-related protein 1 (Drp1) promotes fission of elongated mitochondria. In PX3-treated cells, however, active, phosphorylated Drp1 dropped by half. PX3 probably acts indirectly on Drp1, the authors concluded, since they found no evidence that the two molecules bind. Interestingly, in Alzheimer’s disease, and after rotenone treatment, Drp1 becomes overactive. This causes mitochondria to fragment, precipitating cell death (see Apr 2009 news story). Too little Drp1 also creates problems; a recent study reported that deletion of the protein in mouse dopamine neurons led to loss of mitochondria, axons, and neurons (Berthet et al., 2014).
Gonzalez-Dunia’s data suggest that PX3 protects neurons in a preventative model. Could the peptide also treat ongoing disease? He is investigating this in animals that model chronic, progressive Parkinson’s disease. Because mitochondrial dysfunction characterizes many neurodegenerative disorders, he is also testing PX3 in models of Alzheimer’s and ALS (see Mar 2013 news story; Oct 2014 news story; Oct 2014 news story).
While the consequences of chronic administration of PX3 are unclear, treated mice show no ill effects. Before MPTP administration, neurons maintained normal cellular respiration and had few elongated mitochondria, Gonzalez-Dunia said. “Under normal conditions, cells are not affected by the peptide, but in response to stress, the mitochondria are better armed to respond,” he told Alzforum. He plans to further study the peptide’s pharmacodynamics and potential toxicity. He noted that PX3 itself might not become a therapy; instead, it might point the way toward better peptides or drugs that target the same mechanism.
The protective abilities of BDV and protein X may come as a surprise, since other work suggests pathogens increase risk for neurodegenerative disease (see, e.g., Oct 2004 conference story; Aug 2009 news story). Researchers led by Fredrik Elgh at Umeå University, Sweden, recently found that people infected with the Herpes simplex virus for seven years or more, and those with active Herpes simplex infections, run double the risk of developing AD (see also Feb 2011 webinar). The results appear in two papers in the October Alzheimer’s and Dementia. These data support earlier research by Ruth Itzhaki at the University of Manchester, U.K., who has long championed the idea of a link between HSV infection and AD (see Jun 2004 webinar; Wozniak et al., 2009).
Likewise, Balin has linked infection with the respiratory bacterium Chlamydia pneumoniae to Alzheimer’s onset (see Little et al., 2004; Gérard et al., 2006). Intriguingly, Chlamydia infections also dial down neuronal apoptosis and lead to misshapen, enlarged mitochondria, Balin told Alzforum (see Appelt et al., 2008). He plans to investigate whether Chlamydia makes a protein analogous to BDV’s protein X. “Maybe there is a global [anti-apoptotic] mechanism common to persistent infections in the nervous system,” he speculated.
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