In their quest for a cure for Parkinson’s disease scientists have developed two peptides. These peptides when administered intranasally slowed the death of dopaminergic neurons thereby improving the symptoms of Parkinson’s. Initial results in laboratory mice are very encouraging.
Parkinson’s disease is the most common motor pathology in the world. Millions of people worldwide suffer from this degeneration of dopaminergic neurons, which causes many symptoms, including the characteristic tremor. The culprit of dopaminergic neuronal death is thought to be insoluble aggregates of abnormally shaped α-synuclein, the so-called preformed fibrils. They are also present in Lewy bodies and are the cause of several neurodegenerative diseases, including Parkinson’s disease.
Usually, neurons can eliminate α-synuclein aggregates by exocytosis. These could then be transferred to other neurons by a hitherto unknown mechanism. Microglia, the immune cells of the brain are activated by preformed fibrils and release pro-inflammatory cytokines. Chronic inflammation in the brain accelerates the death of dopaminergic neurons and the release of α-synuclein.
Promising intranasal treatment
Scientists at Rush University Medical Center in Chicago proposed an approach to fix this problem that has proven successful in vitro and now in vivo in laboratory mice. They have developed two peptides, small proteins that inhibit α-synuclein-induced microglial activation. The first, called wtTIDM, targets TLR2, an innate immunity receptor that activates microglia. By preventing TLR2 from communicating with other elements that are responsible for the cascade reaction, the wtTIDM peptide prevents microglial activation. A second peptide, wtNBD, acts in the same way but binds elsewhere.
Both peptides were administered intranasally to mice with a large number of pre-formed fibrils to trigger a form of Parkinson’s disease. Following this treatment, microglia inflammatory activity was significantly reduced, as was α-synuclein propagation, thereby protecting the dopaminergic neurons. This biological effect is reflected in an improvement in health status. The treated mice showed improved locomotor and balance abilities as well as other motor functions.
Human trials are still needed
“If these results can be replicated in patients, it will be a major breakthrough in the treatment of this devastating neurological disorder,” concludes Kalipada Pahana, who led the study which was published in Nature Communications. There are drugs that slow the progression of Parkinson’s disease, such as levodopa, which replenishes the dopamine deficiency caused by neuronal death. It slows the loss of motor skills but does not prevent the death of dopaminergic neurons. For patients with the most severe impairments, deep brain stimulation may be an alternative.
Scientists are currently working on several lines of research, such as immunotherapy and gene therapy, to cure this disease, which we so far can only slow down.