Buck Institute study reveals much broader role for Parkin in cellular dynamics, challenging current dogma in the field.
Rapamycin, an FDA-approved drug that extends lifespan in several species, prevented Parkinson’s disease (PD) in middle-age mice that were genetically fated to develop the incurable neurodegenerative motor disease that affects as many as one million Americans. While the rapamycin did great things for the mice, scientists in the Andersen lab at the Buck Institute also got an unexpected plus from the research – a new understanding of the role parkin plays in cellular dynamics, one that challenges the current dogma in PD research and presents new opportunities for drug discovery. The study is currently online in the Journal of Neuroscience.
“Given its side effects as an immunosuppressant, there are issues with long-term use of rapamycin, but the results of our study suggest that use of derivatives of rapamycin or other agents with similar biological properties may constitute novel therapeutics for the disorder,” said senior scientist and Buck faculty Julie Andersen, PhD. “Our discoveries regarding parkin may provide an even more important therapeutic target for PD.”
Parkin is a protein encoded by the PARK2 gene in humans. Mutations in PARK2 are most commonly linked to both sporadic and familial forms of PD; they diminish the cell’s ability to recycle its internal garbage. PD is characterized by the accumulation of damaged proteins and mitochondria in the area of the brain where the neurotransmitter dopamine is produced.
Rapamycin prevented PD symptoms from occurring in middle-aged mice who had a human mutation in the PARK2 gene. Researchers in the Andersen lab expected this benefit to come via the accepted role of parkin – they thought rapamycin would boost the mutated protein’s ability to label certain types of cellular garbage for recycling. Instead they discovered that parkin plays a much broader role in the actual recycling of garbage and the manufacturing of new mitochondria.
“This is a completely new, unrecognized, function for parkin,” said Andersen. “Our work shows that parkin plays a much broader role than was originally thought in getting rid of damaged mitochondria and proteins. It’s very exciting because it gives us new ways to look at potential therapeutics to boost cellular clean up.”
Working in both neuronal stem cell models and mouse tissue, scientists found that rapamycin not only boosted the mutated protein’s ability to label cellular garbage, but also affected the process of recycling the garbage itself via up-regulation of a protein known as TFEB which increased the degradation and purging of both damaged proteins and mitochondria via a process known as lysosomal autophagy. Apart from rapamycin’s effects, Andersen’s team also discovered that parkin is involved in mitochondrial biogenesis – via up-regulation of PGC1alpha, a protein which drives increased mitochondrial synthesis.
“Problems with autophagy, which result in the accumulation of damaged proteins and organelles, have long been linked to PD,” said Ana Maria Cuervo, MD, PhD, professor and recipient of the Robert and Renée Belfer Chair for the Study of Neurodegenerative Diseases at Albert Einstein College of Medicine in New York City. “This novel role of parkin in the regulation of the overall process of autophagy gives us new ways to address its dysfunction in PD.”
“Researchers are already very interested in parkin as it relates to PD,” said Andersen. “I’m hoping that uncovering this novel role for the protein will bring it center stage as an extremely important therapeutic target for the disorder.”
Funding: Other Buck Institute researchers involved in the study include Almas Siddiqui, Dipa Bhaumik, Shankar Chinta, Anand Rane, Subramanian Rajagopalan, Christopher A. Lieu, and Gordon J. Lithgow. This work was supported by the National Institutes of Health grant AG025901.
Source: Kris Rebillot – Buck Institute for Research on Aging
Image Credit: The image is credited to Shankar Chinta, Ph.D., staff scientist, Buck Institute
Original Research: Abstract for “Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin” by Almas Siddiqui, Dipa Bhaumik, Shankar J. Chinta, Anand Rane, Subramanian Rajagopalan, Christopher A. Lieu, Gordon J. Lithgow, and Julie K. Andersen in Journal of Neuroscience. Published online September 16 2015 doi:10.1523/JNEUROSCI.0109-15.2015
Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin
Following its activation by PINK1, parkin is recruited to depolarized mitochondria where it ubiquitinates outer mitochondrial membrane proteins, initiating lysosomal-mediated degradation of these organelles. Mutations in the gene encoding parkin, PARK2, result in both familial and sporadic forms of Parkinson’s disease (PD) in conjunction with reductions in removal of damaged mitochondria. In contrast to what has been reported for other PARK2 mutations, expression of the Q311X mutation in vivo in mice appears to involve a downstream step in the autophagic pathway at the level of lysosomal function. This coincides with increased PARIS expression and reduced expression of a reciprocal signaling pathway involving the master mitochondrial regulator peroxisome proliferator-activated receptor-gamma coactivator (PGC1α) and the lysosomal regulator transcription factor EB (TFEB). Treatment with rapamycin was found to independently restore PGC1α-TFEB signaling in a manner not requiring parkin activity and to abrogate impairment of mitochondrial quality control and neurodegenerative features associated with this in vivo model. Losses in PGC1α-TFEB signaling in cultured rat DAergic cells expressing the Q311X mutation associated with reduced mitochondrial function and cell viability were found to be PARIS-dependent and to be independently restored by rapamycin in a manner requiring TFEB. Studies in human iPSC-derived neurons demonstrate that TFEB induction can restore mitochondrial function and cell viability in a mitochondrially compromised human cell model. Based on these data, we propose that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via upregulation of TFEB function.
SIGNIFICANCE STATEMENT Mutations in PARK2 are generally associated with loss in ability to interact with PINK1, impacting on autophagic initiation. Our data suggest that, in the case of at least one parkin mutation, Q311X, detrimental effects are due to inhibition at the level of downstream lysosomal function. Mechanistically, this involves elevations in PARIS protein levels and subsequent effects on PGC1α-TFEB signaling that normally regulates mitochondrial quality control. Treatment with rapamycin independently restores PGC1α-TFEB signaling in a manner not requiring parkin activity and abrogates subsequent mitochondrial impairment and neuronal cell loss. Taken in total, our data suggest that the parkin Q311X mutation impacts on mitochondrial quality control via PARIS-mediated regulation of PGC1α-TFEB signaling and that this can be independently restored via rapamycin.
“Mitochondrial Quality Control via the PGC1α-TFEB Signaling Pathway Is Compromised by Parkin Q311X Mutation But Independently Restored by Rapamycin” by Almas Siddiqui, Dipa Bhaumik, Shankar J. Chinta, Anand Rane, Subramanian Rajagopalan, Christopher A. Lieu, Gordon J. Lithgow, and Julie K. Andersen in Journal of Neuroscience. Published online September 16 2015 doi:10.1523/JNEUROSCI.0109-15.2015