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

Study: Amelioration of pathologic α-synuclein-induced Parkinson’s disease by irisin. Image Credit: GP PIXSTOCK/Shutterstock

A latest paper discusses the hope held out by recent results on a compound called irisin, a brief 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. Probably the most characteristic of those is the slowing of movement, tremor at rest, and rigidity, amongst motor symptoms, while the latter category includes each autonomic impairment and neuropsychiatric features.

The underlying lesion appears to be dopaminergic neuron loss within the a part of the brain called the substantia nigra pars compacta (SNpc). One other hallmark is, nevertheless, the piling up of a misfolded protein called α-synuclein, which causes neuronal dysfunction and should be answerable for the final word lack of neurons as well.

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

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

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

Together with its precursor, FNCD5, irisin increases in muscle tissue after several sorts of exercise, including exercise training. In quite a lot 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 sorts of neurodegeneration, including Alzheimer’s disease and PD. The truth is, the authors of this paper showed earlier that with elevated FNDC5 levels within the liver and maybe the blood, the hippocampus appeared to enter an “exercise-like” mode of gene expression.

In one other experiment, FNDC5 expression using a viral vector restored memory in an AD mouse model. Irisin was demonstrated to be the important thing element in cognitive function regulation in 4 different experiments on mice.

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

Since α-synuclein seems to spread like a prion within the brains of patients with PD in addition to another neurologic conditions, causing neuronal dysfunction and death, the researchers checked out the results of irisin on PD pathophysiology when a compound called α-synuclein performed fibril (α-syn PFF) was seeded in cell culture. Furthermore, they checked out the power of irisin to revive normal histology in mouse SNpc and relieve PD-like symptoms after injecting α-syn PFF into the corpus striatum of the brain.

The present study, published online within 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 inside 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 lack of dopaminergic neurons within the corpus striatum after the injection of α-syn PFF into this region of the brain. To show this, a viral vector was used to introduce mature cleaved irisin into the liver and thence to the bloodstream. This has been shown to extend brain irisin levels to a level adequate to mitigate AD-like changes in two different mouse models, though the virus itself doesn’t infect the brain or express itself on this organ.

As expected, the α-syn spread inside 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 in comparison with 60% when the identical viral vector was injected without irisin.

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

Still more significantly, irisin blocked the buildup of α-syn PFF and α-syn as well within the irisin-treated mice, though soluble α-syn monomers remained detectable at the identical 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. One other 26 proteins showed changes at day 4, but over a 3rd of those changes disappeared with irisin treatment.

Overall, in comparison with 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 within the α-syn level itself. A vital change with α-syn exposure was the rise in ApoE protein expression because the ε4 gene type of this protein is linked to α-syn pathology and dementia risk in individuals with PD and AD. Irisin produced the alternative effect on this gene.

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

Irisin also promotes the breakdown of this pathologic protein inside 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 ends in neurodegeneration. Nevertheless, when treated with irisin, the degrees of α-syn within the lysosomes were markedly lower as a consequence of 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 appears to be via increased lysosomal destruction of this abnormal protein.

This supports earlier studies showing that irisin promotes autophagy inside lysosomes. While irisin acts to manage brain peptides and glial activation levels to stop brain damage when exposed to certain toxins, this doesn’t look like the first mode of protection in disorders like PD which might be linked to α-syn accumulation and the following cascade of neurologic damage.

This doesn’t mean that irisin can arrest the progression of the disease or reverse already existing damage. Further research is required to grasp the potential of this compound in PD, given the proven 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’s considerable promise that it is likely to be developed as a disease-modifying therapy for the treatment of PD.”