Summary: A new PNAS study reveals an FDA approved drug that targets toxic protein interactions could be used as a novel treatment for Parkinson’s disease.
Source: Northwestern University.
A new study, published in Proceedings of the National Academy of Sciences (PNAS), sheds light on a mechanism underlying Parkinson’s disease and suggests that Tacrolimus — an existing drug that targets the toxic protein interaction explored in the study — could be used as a novel treatment.
Gabriela Caraveo Piso, PhD, assistant professor of Neurology in the Division of Movement Disorders, was the first and corresponding author of the study.
Parkinson’s disease is a progressive neurological disorder marked by the loss of dopaminergic neurons. There is no cure, and current treatments to help control the symptoms of Parkinson’s — including tremor, slow movement and loss of balance — are limited.
Although the fundamental cause of Parkinson’s disease is unknown, dysfunction of a protein called alpha-synuclein has long been thought to play an important role.
Previous investigations by Caraveo Piso and collaborators had established that increased activity of an enzyme called calcineurin is associated with the alpha-synuclein toxicity seen in Parkinson’s.
In the current study, the scientists built upon those discoveries to demonstrate, for the first time, that a protein called FKBP12 is a major regulator of calcineurin activity, and thus contributes to alpha-synuclein toxicity.
“Our new mechanistic findings have revealed that FKBP12 is the protein that tunes calcineurin activity,” Caraveo Piso said. “It’s very reminiscent of the Goldilocks story: In the context of alpha-synuclein, both too much and no calcineurin activity are detrimental — but an intermediate level of activity is protective.”
The scientists also investigated whether reducing the functional interaction between calcineurin and FKBP12 might be protective against alpha-synuclein toxicity in vivo.
To do so, they employed an already well-established, FDA-approved inhibitor of this interaction, called Tacrolimus. The drug is currently used clinically in high doses to prevent organ rejection after a transplant, a process in which calcineurin also plays a critical role.
In an animal model of Parkinson’s disease, the investigators demonstrated that Tacrolimus — when administered in low doses to achieve partial reduction of calcineurin activity — led to improvements in the functional features of dopaminergic neurons, and hence behavioral phenotypes.
Caraveo Piso noted that the discovery has strong potential for future clinical applications.
“We provide robust animal evidence for a feasible treatment against Parkinson’s by repurposing Tacrolimus at low, sub-immunosuppressive doses,” Caraveo Piso said. “Since Tacrolimus has high brain penetrance and can be given safely, a clinical trial of Tacrolimus in patients with early-stage Parkinson’s would likely pose no serious logistical or regulatory difficulties.”
The findings might also have implications for other related neurological diseases, such as Alzheimer’s, Caraveo Piso notes, an area where calcineurin also plays an important role.
Sofia Zaichick, MD, PhD, a research associate in Caraveo Piso’s lab, was also a co-author of the paper.
Susan Lindquist, PhD, the senior author, was previously a professor of Biology at The Massachusetts Institute of Technology and director of the Whitehead Institute for Biomedical Research, where Caraveo Piso conducted most of the study as a postdoctoral associate before joining Northwestern.
Funding: The study was supported by funds from the Jeffry M. and Barbara Picower Foundation, funds from the RJG Foundation–Judy Goldberg, a Howard Hughes Medical Institute (HHMI) Collaborative Innovation Award, National Institutes of Health grant 5P50NS38372, WIBR funds for the study of regenerative biology, and a gift from Ofer Nemirovsky.
Source: Anna Williams – Northwestern University
Publisher: Organized by NeuroscienceNews.com.
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Original Research: Full open access research for “FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome” by Gabriela Caraveo, Martin Soste, Valentina Cappelleti, Saranna Fanning, Damian B. van Rossum, Luke Whitesell, Yanmei Huang, Chee Yeun Chung, Valeriya Baru, Sofia Zaichick, Paola Picotti, and Susan Lindquist in PNAS. Published online December 11 2017 doi:10.1073/pnas.1711926115
FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome
Calcineurin is an essential Ca2+-dependent phosphatase. Increased calcineurin activity is associated with α-synuclein (α-syn) toxicity, a protein implicated in Parkinson’s Disease (PD) and other neurodegenerative diseases. Calcineurin can be inhibited with Tacrolimus through the recruitment and inhibition of the 12-kDa cis-trans proline isomerase FK506-binding protein (FKBP12). Whether calcineurin/FKBP12 represents a native physiologically relevant assembly that occurs in the absence of pharmacological perturbation has remained elusive. We leveraged α-syn as a model to interrogate whether FKBP12 plays a role in regulating calcineurin activity in the absence of Tacrolimus. We show that FKBP12 profoundly affects the calcineurin-dependent phosphoproteome, promoting the dephosphorylation of a subset of proteins that contributes to α-syn toxicity. Using a rat model of PD, partial elimination of the functional interaction between FKBP12 and calcineurin, with low doses of the Food and Drug Administration (FDA)-approved compound Tacrolimus, blocks calcineurin’s activity toward those proteins and protects against the toxic hallmarks of α-syn pathology. Thus, FKBP12 can endogenously regulate calcineurin activity with therapeutic implications for the treatment of PD.
“FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome” by Gabriela Caraveo, Martin Soste, Valentina Cappelleti, Saranna Fanning, Damian B. van Rossum, Luke Whitesell, Yanmei Huang, Chee Yeun Chung, Valeriya Baru, Sofia Zaichick, Paola Picotti, and Susan Lindquist in PNAS. Published online December 11 2017 doi:10.1073/pnas.1711926115