Disease Twofer: Parkin Problem Leads To Parkinson’S And Impairs Response To TB

University of California, San Francisco researchers report that a key protein associated with Parkinson's disease also plays a major role in the destruction of the bacteria that cause tuberculosis.

Malfunctioning of the Parkin protein has already been tied to the loss of nerve cells, which leads to Parkinson's. UCSF's Jeffery Cox, Ph.D., and his collaborators now say that Parkin also acts on tuberculosis, triggering destruction of Mycobacterium tuberculosis by macrophages. Results of their study ("The ubiquitin ligase Parkin mediates resistance to intracellular pathogens") appear online today in Nature.

The finding suggests that disease-fighting strategies currently under investigation in preclinical studies for Parkinson's disease might also prove useful in attacking tuberculosis, according to Dr. Cox, who is working on increasing the activity of Parkin in TB-infected mice. Dr. Cox focused on the enzyme Parkin as a common element in Parkinson's and tuberculosis through his studies of how macrophages engulf and destroy bacteria (xenophagy).

M. tuberculosis initially invades the macrophage, but then becomes engulfed in a sac within the macrophage that is pinched off from the cell's outer membrane. The bacteria often escape by secreting a protein that degrades the sac, only to be targeted yet again by molecular chains made from another protein (ubiquitin). Previously, Dr. Cox discovered molecules that escort these chained mycobacteria to more secure confinement within lysosomes, where the bacteria are destroyed.

The cells of nonbacterial organisms ranging in complexity from baker's yeast to humans also use a similar mechanism-;called autophagy-;to dispose of their own unneeded molecules or worn out cellular components. Among the most abundant and crucial of these components are the cell's mitochondria.

Like other cellular components, mitochondria can wear out and malfunction, and often require replacement. The process through which mitochondria are disposed of (mitophagy) depends on Parkin.

Dr. Cox became curious about the enzyme when he learned that polymorphisms in the Parkin gene are associated with increased susceptibility to tuberculosis infection. "Because of the commonalities between mitophagy and the xenophagy of intracellular mycobacteria, as well as the links between Parkin gene polymorphisms and increased susceptibility to bacterial infection in humans, we speculated that Parkin may also be recruited to M. tuberculosis, [targeting] it for xenophagy," Dr. Cox said.

In both mouse and human macrophages infected with M. tuberculosis in the lab, Parkin played a key role in fighting the bacteria In addition, genetically engineered mice lacking Parkin died when infected with M. tuberculosis, while mice with normal Parkin survived infection.

The involvement of Parkin in targeting both damaged mitochondria and infectious mycobacteria arose long ago in evolution, according to Dr. Cox.

"Our findings reveal that Parkin regulates a common cellular program by which metazoans [multicellular animals] mediate quality control of endogenous mitochondria (self) and eradicate harmful bacterial pathogens (nonself)," he and his colleagues wrote in the Nature article. "Although these two activities are seemingly disparate, the evolutionary origin of mitochondria from a bacterial endosymbiont suggests that perhaps mitochondrial dysfunction triggers the recognition of the organelle as nonself."

Having now demonstrated the importance of Parkin in fighting mycobacterial infection, Dr. Cox has begun working with UCSF's Kevan Shokat, Ph.D., to find a way to boost Parkin activity against cell-invading bacteria.

"We are exploring the possibility that small-molecule drugs could be developed to activate Parkin to better fight tuberculosis infection," explained Dr. Cox.

Summarizing the team's work, Dr. Cox and his colleagues write that "This work highlights the unexpected connection between mitochondrial-based neuronal disorders and susceptibility to bacterial infection in humans. Recent genome-wide association studies on inflammatory bowel disease, which is linked to altered hostgut microbe interactions, have identified susceptibility single nucleotide polymoprhisms within LRRK2 and PARK7, two genes canonically associated with Parkinson's disease. Thus, we surmise that genes typically associated with neuronal maintenance or mitophagy may have broad roles in cellular homeostasis within various cell types."

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