Parkinson’s Disease: Catching the Early—and small—Signs

Researchers from Tel Aviv University have developed a new method, which may assist physicians in diagnosing Parkinson’s disease and even treating it in its early stages. The method is based on a new microscopic technique, enabling the identification of protein aggregates that are the hallmark of the disease—while these are still very small.

Prof. Uri Ashery, head of Tel Aviv University’s Sagol School of Neuroscience, and Dr. Dana Bar-On led the research team, which collaborated with laboratories in Cambridge University in England, the Max Planck Institute in Gottingen, and Ludwig Maximilian University in Munich, Germany. The results of the study were published in a June 5 article in the journal Acta Neuropathologica, considered the leading journal in the field of neurologic diseases.

“The brains of Parkinson’s patients are characterized by an accumulation of large aggregates of a certain protein,” explains Prof. Ashery. “The aggregates are linked to a gradual process, in which cells in an area of the mid brain called the substantia nigra (‘black substance’ in Latin) start to die. The loss of these cells causes a decrease in the secretion of the neurotransmitter dopamine in the brain, leading to motor, and later, also cognitive, difficulties. The problem is that current methods enable the detection of the protein aggregates only when these are relatively large, that is, in an advanced stage of the disease, when 75% of the cells in the substantia nigra have already died, and effectively too late for treatment. We looked for a way to diagnose Parkinson’s at a much earlier stage, and also tested a possible treatment for the debilitating disease, considered incurable today.”

Small, multiplying aggregates

The research partners in Cambridge genetically engineered mice to express a mutant form of the human protein found in aggregates in the brains of deceased patients. This form of the protein spontaneously led to the rapid deposition of the aggregates and the development of Parkinson’s disease symptoms. Using advanced super-resolution microscopy, the researchers analyzed sections from the mice’s brains. “We found that small aggregates of a protein called alpha-synuclein appeared in substantia nigra cells in an early stage of the disease,” says Dr. Bar-On. “We also discovered that these small aggregates multiply as the disease progresses, in contrast to the better-known large aggregates, whose number remained constant.”

The small aggregates appeared in the cells of the substantia nigra when the mice were only one-and-a-half month old, but the decrease in the number of cells in the area ensued only after the age of 12 months, with a turn for the worse at 20 months. These cells secrete dopamine to another area in the brain, called the striatum, where a drop in dopamine levels was observed even earlier—at six months of age—also gradually worsening. This finding reflects the fact that damage to nerve synapses in which dopamine is secreted occurs prior to the death of the dopamine-secreting cells themselves.

Respectively, the motor symptoms associated with Parkinson’s disease, such as tremors and bradykinesia (slowness of movement), began at the age of nine months and exacerbated with age. “Because of the age-related decline that began with the death of the cells, the decrease of dopamine secretion, and behavioral symptoms, we concluded that the small aggregates, the only ones that multiply with age, are the toxic compound causing the disease,” says Dr. Bar-On.

An early-stage treatment

The mouse model used by the researchers, combined with the advanced microscopy technique, enables the detection of changes in alpha-synuclein that begin at an early age and progress with time. It thus simulates the human disease—in contrast to other models, in which cells die at an early age but a deterioration over time is not observed. Consequently, this model is suitable to test the effectiveness of medication even at an early disease stage.

On the basis of previous findings, Christian Griesinger, a research collaborator from the Max Planck Institute in Germany who specializes in developing aggregation-inhibiting compounds, designed a compound that inhibits the formation of alpha-synuclein aggregates. The drug was delivered to the model mice through their food, starting at nine months of age, when a decrease in dopamine secretion was identified, until the age of 12 months, when 30% of the cells in the substantia nigra have already died in the untreated mice.

The drug repaired the decrease in dopamine secretion in the striatum and the number of cells in the substantia nigra, so that they maintained the appearance of the cells in normal, umutated mice. The mice also maintained their normal functioning. The drug accomplished this by binding the small, dense protein aggregates, thus effectively preventing their development: Microscopic observation showed that the drug led to a decrease in aggregate density, which apparently also decreased their toxicity. This comes as another testimony to these aggregates’ responsibility for the defects observed in the Parkinson’s mouse model, and possibly also to those observed in human patients.

“We have uncovered a central process in Parkinson’s disease, which was unknown until now, and have also found a compound that neutralizes it, which could serve as the basis for the development of a drug,” summarizes Prof. Ashery. “The potential drug is currently undergoing clinical trials. We are now seeking ways to detect small alpha-synuclein aggregates in humans in the disease’s early stages. Since the analysis of live human brains is not possible, we are searching for these aggregates in other, more accessible body tissues, such as the skin, or secretions, such as tears.”

Dr. Bar-On adds: “The mouse model used in the study combines all the symptoms of the disease in a gradual and spontaneous manner, unlike models that require the injection of fibril structures into the brain and damage the blood-brain barrier, or models based on mutations that appear only in a very small percent of the patients. There is great significance for a model simulating the sporadic appearance of the disease, which represents the majority of Parkinson’s cases.”