Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. It has no definitive cure despite tremendous efforts involving multiple types of targeted drugs and candidates.
A new paper discusses the hope borne by recent findings of a compound called irisin, a short protein secreted by skeletal muscle that produces some exercise-related effects on the brain.
Parkinsonism includes a chronic progressive neurological syndrome, including motor and non-motor symptoms. Slowness of movement, tremors at rest, and rigidity are most distinguished among the motor symptoms, while the latter category includes both autonomic weakness and neuropsychiatric features.
The underlying lesion appears to be the loss of dopaminergic neurons in a part of the brain called the substantia nigra pars compacta (SNPC). However, another distinguishing feature is the accumulation of an unfolded protein called α-synuclein, which causes neuronal dysfunction and may be responsible for the eventual loss of neurons as well.
Compounds that replace dopamine in the brain, including L-dopa, dopamine agonists, and dopamine-releasing inhibitors, are used to control the motor symptoms of PD, while other features are treated with other drugs. Deep brain stimulation is an example of neurosurgical approaches for advanced Parkinson’s disease.
Despite the best treatment, the progressive nature of the disorder remains unchanged, its rate of progression and the underlying pathophysiology remain the same. Eventually, most patients reach a state of functional decline.
Previous research identified the role of irisin in animals and humans as a small polypeptide with similar sequences in mice and humans. This highly conserved nature indicates that its function is essential to normal physiology.
Besides its predecessor, FNCD5, irisin is increased in muscle tissue after several types of exercise, including exercise training. In a variety of tissues, including bone, fat, and astrocytes, the iris acts on the αV/β5 integrin receptor.
The potential role of irisin in Parkinson’s disease has been explored in recognition of the role that physical activity plays in several types of neurodegeneration, including Alzheimer’s disease and Parkinson’s disease. In fact, the authors of this paper showed earlier that with elevated levels of FNDC5 in the liver and possibly the blood, the hippocampus appears to enter an “exercise-like” mode of gene expression.
In another experiment, expression of FNDC5 using a viral vector restored memory in an AD mouse model. Irisin has been demonstrated to be the key component in regulating cognitive function in four different experiments with mice.
Again, increased levels of iris cleft were associated with better cognition and lower levels of neuroinflammation in mice with Alzheimer’s disease. Irisin was able to cross the blood-brain barrier (BBB) as well.
Because α-synuclein appears to proliferate like a prion in the brains of patients with Parkinson’s as well as some other neurological conditions, causing neuronal malfunction and death, researchers looked at the effects of iris on the pathophysiology of PD when a compound called α-synuclein fibril (α-syn PFF) was cultured in cell culture. Furthermore, they looked at the ability of the iris to restore normal tissue in SNPC mice and alleviate PD-like symptoms after injection of α-syn PFF into the striatum.
The current study is published online in the journal PNASexplores the potential role of irisin in Parkinson’s and other neurodegenerative conditions involving α-syn.
What did the study show?
The results of this study indicate that the presence of irisin inhibits the formation of α-syn within neurons after exposure to α-syn PFF, leading to misfolding of this protein into a toxic compound. This protects the neurons from the toxic effects of α-syn PFF.
Irisin also prevented the loss of dopaminergic neurons in the striatum after α-syn PFF was injected into this brain region. To demonstrate this, a viral vector was used to introduce mature cleaved irisin into the liver and then into the bloodstream. This has been shown to increase brain iris levels to a level appropriate to ameliorate Alzheimer’s-like changes in two different mouse models, even though the virus itself does not infect the brain or express itself in this organ.
As expected, α-syn proliferated within the substantia nigra one month after injection, and six months after injection, about half of the dopaminergic neurons were 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 further rescued. Although their levels were reduced by half in mice injected with α-syn PFF, they were restored to only 6% lower than normal by irisin injection. Irisin also prevented a decrease in dopamine/dopamine metabolites from 70% to 95%, depending on the compound measured, while also preventing dopamine turnover.
Importantly, irisin prevented the accumulation of α-syn PFF and α-syn also in irisin-treated mice, although soluble α-syn monomers remained detectable at the same levels. It also prevented the onset of α-syn PFF-mediated behavioral effects of lethal damage.
How did this happen? The researchers examined the protein composition of cells treated with α-syn PFF using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Two proteins showed different levels on the first day after PFF exposure after α-syn, but this was completely suppressed by irisin. Another 26 proteins showed changes on day 4, but more than a third of these changes disappeared with irisin treatment.
Overall, compared to exposure to α-syn PFF alone, cells subsequently treated with irisin showed significant changes in 22 and 15 proteins on day 1 and day 4 of the initial exposure, including a decrease in the level of α-syn itself. An important change with exposure to α-syn was the increase in ApoE protein expression since the ε4 gene variant of this protein is associated with α-syn pathology and risk of dementia in people with Parkinson’s disease and Alzheimer’s disease. Irisin produced the opposite effect on this gene.
“These data suggest that irisin may prevent the intracellular accumulation of a pathological form of α-syn by decreasing its internalization and aggregation.. “
Irisin also enhances the breakdown of this pathological protein within the lysosomes of neurons, as α-syn PFF is taken up by various mechanisms. Normally, this polypeptide forms an α-syn to trigger a chain of events that leads to neurodegeneration. However, when treated with irisin, α-syn levels in lysosomes were significantly lower due to lysosomal degradation.
What are the conclusions?
The researchers concluded that “irisin prevents degeneration of DA neurons and thus reduces motor deficits caused by pathological α-syn. This appears to occur through increased particle destruction of this abnormal protein.
This supports previous studies showing that irisin enhances autophagy within lysosomes. While irisin acts to regulate brain peptides and levels of glial activation to prevent brain damage upon exposure to certain toxins, this does not appear to be the primary mode of protection in disorders such as PD associated with α-syn accumulation and subsequent neuronal cascade damage.
This does not mean that irisin can stop disease progression or reverse existing damage. Further research is required to understand the potential of this compound in PD, given the fact that administration of irisin long after the onset of brain pathology after α-syn injection is still successful in attenuating the deleterious changes and restoring neurobehavioral function.
There is great promise that it can be developed as a disease-modifying therapy for Parkinson’s disease. “