Exercise hormone irisin blocks Parkinson's-associated α-synuclein aggregation and related neuronal toxicity

By Dr. Liji Thomas, MDSep 15 2022Reviewed by Danielle Ellis, B.Sc.

Parkinson’s disease (PD) is among the most common neurodegenerative disorders. It has no definitive treatment despite herculean efforts encompassing multiple types of drug targets and candidates.

A new paper discusses the hope held out by recent results on a compound called irisin, a short protein secreted by skeletal muscle that produces some exercise-related effects on the brain.

Introduction

PD comprises a chronic progressive neurologic syndrome, including motor and non-motor symptoms. The most characteristic of these is the slowing of movement, tremor at rest, and rigidity, among motor symptoms, while the latter category includes both autonomic impairment and neuropsychiatric features.

The underlying lesion appears to be dopaminergic neuron loss in the part of the brain called the substantia nigra pars compacta (SNpc). Another hallmark is, however, the piling up of a misfolded protein called α-synuclein, which causes neuronal dysfunction and may be responsible for the ultimate loss of neurons as well.

Compounds that replace dopamine in the brain, including L-dopa, dopamine agonists, and inhibitors of dopamine breakdown, are typically used to control PD motor symptoms, while the other features are treated using other drugs. Deep brain stimulation is an example of neurosurgical approaches to advanced PD.

Despite the best treatment, the progressive nature of the disorder remains unchanged, and its progression rate and underlying pathophysiology remain intact. Eventually, therefore, most patients reach a state of functional decline.

Earlier research identified the role of irisin in animals and humans as a small polypeptide with an identical sequence in mice and humans. This highly conserved nature suggests that its function is crucial to normal physiology.

Along with its precursor, FNCD5, irisin increases in muscle tissue after several types of exercise, including exercise training. In a variety of tissues, including bone, fat, and astrocytes, irisin acts on the integrin αV/β5 receptor.

The potential role of irisin in PD was explored in recognition of the role played by physical activity in several types of neurodegeneration, including Alzheimer’s disease and PD. In fact, the authors of this paper showed earlier that with elevated FNDC5 levels in the liver and perhaps the blood, the hippocampus appeared to go into an “exercise-like” mode of gene expression.

In another experiment, FNDC5 expression using a viral vector restored memory in an AD mouse model. Irisin was demonstrated to be the key element in cognitive function regulation in four different experiments on mice.

Again, increased cleaved irisin levels were associated with better cognition and lower levels of neuroinflammation in mice with AD. Irisin was able to cross the blood-brain barrier (BBB) as well.

Since α-synuclein seems to spread like a prion in the brains of patients with PD as well as some other neurologic conditions, causing neuronal dysfunction and death, the researchers looked at the effects of irisin on PD pathophysiology when a compound called α-synuclein performed fibril (α-syn PFF) was seeded in cell culture. Moreover, they looked at the ability of irisin to restore normal histology in mouse SNpc and relieve PD-like symptoms after injecting α-syn PFF into the corpus striatum of the brain.

The current study, published online in the journal PNAS, explores the potential role of irisin in PD and other neurodegenerative states that involve α-syn.

What did the study show?

The findings of this study indicate that the presence of irisin prevents α-syn formation within neurons following their exposure to α-syn PFF, which induces misfolding of this protein to a toxic compound. This protected the nerve cells against the toxic effects of α-syn PFF.

Irisin also prevented the loss of dopaminergic neurons in the corpus striatum after the injection of α-syn PFF into this region of the brain. To demonstrate this, a viral vector was used to introduce mature cleaved irisin into the liver and thence to the bloodstream. This has been shown to increase brain irisin levels to a level adequate to mitigate AD-like changes in two different mouse models, though the virus itself does not infect the brain or express itself in this organ.

As expected, the α-syn spread within the substantia nigra by one month following injection, and at six months from injection, about half the dopaminergic neurons had been lost in these mice. In contrast, irisin rescued these neurons, with only a 25% loss compared to 60% when the same viral vector was injected without irisin.

The enzyme and transporter involved in dopamine transmission in this region were rescued still more significantly. Though their levels dropped by half in the mice injected with α-syn PFF, this was restored to just 6% less than normal by irisin injection. Irisin also prevented a decrease in the dopamine/dopamine metabolites by 70% to 95%, depending on the compound measured, with dopamine turnover being suppressed.

Still more significantly, irisin blocked the accumulation of α-syn PFF and α-syn as well in the irisin-treated mice, though soluble α-syn monomers remained detectable at the same levels. It also prevented the emergence of the behavioral effects of α-syn PFF mediated by striatal damage.

How did this occur? The researchers examined the protein composition of the α-syn PFF-treated cells using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Two proteins showed different levels at day 1 post-α-syn PFF exposure, but this was completely suppressed by irisin. Another 26 proteins showed changes at day 4, but over a third of these changes disappeared with irisin treatment.

Overall, compared to α-syn PFF exposure alone, cells subsequently treated with irisin showed marked changes in 22 and 15 proteins on day 1 and day 4 from initial exposure, including a decrease in the α-syn level itself. An important change with α-syn exposure was the increase in ApoE protein expression since the ε4 gene form of this protein is linked to α-syn pathology and dementia risk in people with PD and AD. Irisin produced the opposite effect on this gene.

“These data suggest that irisin may prevent the intracellular accumulation of a pathologic form of α-syn by decreasing its internalization and aggregation.”

Irisin also promotes the breakdown of this pathologic protein within the lysosomes of the neurons, where α-syn PFF is taken up by various mechanisms. Normally, this polypeptide forms α-syn to trigger a cascade of events that results in neurodegeneration. However, when treated with irisin, the levels of α-syn in the lysosomes were markedly lower due to lysosomal degradation.

What are the conclusions?

The researchers concluded that “irisin prevents the degeneration of DA neurons and thereby reduces the motor deficits induced by pathologic α-syn.” This seems to be via increased lysosomal destruction of this abnormal protein.

This supports earlier studies showing that irisin promotes autophagy within lysosomes. While irisin acts to regulate brain peptides and glial activation levels to prevent brain damage when exposed to certain toxins, this does not appear to be the primary mode of protection in disorders like PD that are linked to α-syn accumulation and the subsequent cascade of neurologic damage.

This does not mean that irisin can arrest the progression of the disease or reverse already existing damage. Further research is required to understand the potential of this compound in PD, given the fact that irisin administration well after the onset of brain pathology following α-syn injection still succeeded in mitigating the deleterious changes and restoring neurobehavioral function.

There is considerable promise that it might be developed as a disease-modifying therapy for the treatment of PD.”