Treatment to Prevent Transplant Rejection Seen to Hold Promise in Parkinson’s Study

Treatment to Prevent Transplant Rejection Seen to Hold Promise in Parkinson’s Study
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A treatment widely used to help prevent rejection in organ transplants, called tacrolimus, appears to work to treat Parkinson’s disease (PD) and ideally should be tested in early-stage patients, researchers report.

Tacrolimus, marketed under brand names including Prograf, works to suppress the immune system. It is used at high dose with other medications to dampen the likelihood of rejection in people who underwent a kidney, liver, or heart transplant.

Importantly, it is known to block the activity of an enzyme called calcineurin, which previous research by the team behind this study found to be connected to the alpha-synuclein toxicity observed in Parkinson’s. Alpha-synuclein (α-synuclein), a protein, is a major constituent of Lewy bodies, the protein clumps that are the pathological hallmark of Parkinson’s disease.

Building on this knowledge, the team — led by Gabriela Caraveo Piso, an assistant neurology professor at Northwestern University’s Feinberg School of Medicine — now found that calcineurin activity is regulated by a protein called FKBP12, and their interaction contributes to the toxic effects of α-synuclein aggregates.

Tacrolimus is a known and FDA-approved inhibitor of FKBP12 and calcineurin.

After positive findings in lab studies that included yeast cells and cortical neurons from rat embryos, the researchers turned to an animal model of Parkinson’s (rats). Again, they showed that tacrolimus helped to reduce calcineurin activity, so as to improve the workings of dopaminergic neurons and ease behaviors associated with the disease.

“Our new mechanistic findings have revealed that FKBP12 is the protein that tunes calcineurin activity,” Caraveo Piso said in a university press release. “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.”

Importantly, the low dose used did not overly suppress the animals’ immune system.

“We provide robust animal evidence for a feasible treatment against Parkinson’s by repurposing Tacrolimus at low, sub-immunosuppressive doses,” he 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, which were reported in the study “FKBP12 contributes to α-synuclein toxicity by regulating the calcineurin-dependent phosphoproteome,” highlight both the important role of calcineurin and FKBP12 in Parkinson’s and therapeutic potential of tacrolimus for this and other α-synuclein-related disorders.

Researchers suggest this work relevant to other neurological diseases in which calcineurin plays an important role, such as Alzheimer’s. Their study was published in Proceedings of the National Academy of Sciences (PNAS).

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