Therapeutics

Turning Exercise Biology into a Therapeutic Candidate for Parkinson’s Disease

An unexpected discovery from exercise biology has led to irisin, a muscle‑derived hormone now being developed as a potential disease‑modifying therapy for Parkinson’s disease.

There may soon be new hope for people living with Parkinson’s disease, a progressive neurological condition for which there is currently no cure. A discovery by Bruce Spiegelman, PhD, a researcher at the Dana‑Farber Cancer Institute, and his colleagues led to the identification of irisin—a muscle‑derived hormone released during exercise that shows encouraging signs of slowing Parkinson’s disease progression in preclinical models. Dana‑Farber has licensed the discovery to Aevum Therapeutics, which is now developing engineered forms of irisin with the goal of advancing a disease‑modifying treatment for people with Parkinson’s.

An Accidental Starting Point

The discovery of irisin began in 2002, when Spiegelman’s lab introduced the transcriptional coactivator PGC‑1α into mouse skeletal muscle to study how it influences energy metabolism. PGC‑1α functions as a kind of “master switch,” helping muscle cells adapt to changing energy demands, particularly during exercise. When the team activated it artificially, the results were unexpected: without exercising at all, the mice developed high‑endurance, oxidative “red muscle,” closely resembling the physiological changes seen after sustained aerobic training.

This surprising transformation suggested that PGC‑1α had triggered a broader, exercise‑like program inside muscle tissue. To understand what signals might be leaving the muscle under these conditions, Spiegelman’s team studied proteins released by muscle into the blood of the engineered mice, compared with those in normal controls. Among the differences was a small, previously unrecognized protein fragment released systemically. The researchers named it irisin.

Initial studies focused on irisin’s effects on fat and bone biology. Over time, however, the lab began to uncover evidence that irisin affects more fundamental cellular processes. As links emerged between irisin and pathways involved in protein quality control, its potential relevance to neurodegenerative disease came into sharper focus—particularly for conditions marked by toxic protein accumulation, such as Parkinson’s disease.

A Mechanism Relevant to Parkinson’s Disease

Parkinson’s disease is characterized by the accumulation of a protein called alpha‑synuclein inside neurons. Under normal conditions, alpha‑synuclein is a small, flexible protein found throughout the brain, where it plays a role in synaptic signaling. In Parkinson’s, however, the protein misfolds and aggregates, forming toxic clumps that disrupt cellular function and ultimately contribute to neuronal death.

“Parkinson’s disease appears to result from the collection of toxic protein aggregates within cells,” Spiegelman explains. “Either too much garbage is being produced, or the trash‑removal system is too slow—and that kills neurons.”

Against that backdrop, Spiegelman’s group found that irisin activates pathways that enhance the cell’s internal cleanup machinery. By strengthening systems responsible for identifying and degrading misfolded or damaged proteins, irisin improves a neuron’s ability to clear alpha‑synuclein before it accumulates to harmful levels.

In cell‑culture experiments, neurons exposed to alpha‑synuclein formed far fewer toxic aggregates when irisin was present. In mouse models of Parkinson’s disease, irisin treatment halted the progression of behavioral deficits and reduced pathological features of the disease.

In mice, irisin stops the disease from getting worse. That’s something current Parkinson’s therapies simply don’t do. We will soon find out of it can also reverse damage that has already be done.

Bruce Spiegelman, PhD

These findings were first reported in a 2022 study published in Proceedings of the National Academy of Sciences, co‑led by Spiegelman and Ted Dawson, MD, PhD, of Johns Hopkins University. The study provided the first evidence that irisin can arrest disease progression in established Parkinson’s disease models, supporting its potential as a disease‑modifying therapy rather than a symptomatic treatment.

As the work progressed, a 2023 study published in Molecular Cell identified the integrin receptor through which irisin signals, revealing a two‑step mechanism involving extracellular Hsp90α. Identifying the receptor clarified how irisin exerts its neuroprotective effects and strengthened the biological foundation needed to support therapeutic development.

While irisin may or may not reverse neuron loss that had already occurred, its ability to slow or stop disease progression in these models suggests disease‑modifying potential—an important distinction from current Parkinson’s therapies, which largely focus on symptom management.

“In mice, irisin stops the disease from getting worse,” Spiegelman stresses. “That’s something current Parkinson’s therapies simply don’t do. We will soon find out of it can also reverse damage that has already be done.”

Building a Translational Scientific Network

As the Parkinson’s work deepened, advancing irisin from a biological signal to a therapeutic concept required a broad and coordinated scientific effort. Spiegelman’s laboratory continued to lead the molecular and mechanistic work, while in vivo validation relied on a long‑standing collaboration with Dawson, whose group brought deep expertise in Parkinson’s pathology and animal models.

Within Dana‑Farber, the project expanded into a focused internal network. Mu A., PhD, an instructor in the Spiegelman Lab, emerged as a central contributor as the research moved more deeply into neurodegeneration, leading many of the cell‑based and mechanistic studies. In parallel, Kate Blackmore, PhD, explored early findings suggesting that irisin might also influence cancer biology, working with Jennifer Ligibel, MD, director of the Zakim Center. Edward Chouchani, PhD, contributed additional insight through his expertise in metabolism and mitochondrial signaling.

Together, these efforts formed a translational framework in which mechanistic discovery, disease modeling, and exploratory biology advanced in parallel.

Sustaining Long‑Term Discovery

Early work was supported by the National Institutes of Health and by long‑term philanthropic funding from the FTF (formerly Picower) Foundation, which encouraged fundamental exploration of muscle biology and energy metabolism. More recently, a substantial gift from the Tyler Family Foundation accelerated Parkinson’s‑focused research in Spiegelman’s lab, enabling deeper mechanistic studies and expanded in vivo validation at a critical moment in the program’s evolution.

From Discovery to Licensing

As evidence accumulated that irisin directly influences protein quality‑control pathways central to Parkinson’s disease, Spiegelman was approached by an entrepreneur interested in developing therapeutics inspired by exercise biology. He brought the opportunity to Lou Tartaglia, PhD, managing partner of Cure VC and a longtime collaborator with Spiegelman, who became a founding investor and acting chief scientific officer of the new venture.

Dana‑Farber subsequently licensed the irisin intellectual property to Aevum Therapeutics, where it is now undergoing preclinical optimization with several engineered, long‑acting irisin molecules under development.

“Aevum’s goal is to nominate a clinical candidate capable of targeting the biological drivers of Parkinson’s disease and halting its progression—and perhaps even reversing certain aspects of this terrible disease,” Spiegelman says.

Team Members: Jennifer Ligibel, MD, Kate Blackmore, PhD, Mu A., PhD, Ted Dawson, MD, PhD, Bruce Spiegelman, PhD, Edward Chouchani, PhD

Team Members