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The genetic mutation causes an enzyme called leucine-rich repeat kinase 2, or LRRK2, to be overactive. Too much LRRK2 enzyme activity changes the structure of brain cells in a way that disrupts crucial communication between neurons that make the neurotransmitter dopamine and cells in the striatum, a region deep in the brain that is part of the dopamine system and is involved in movement, motivation and decision making.

“Findings from this study suggest that inhibiting the LRRK2 enzyme could stabilize the progression of symptoms if patients can be identified early enough,” said Suzanne Pfeffer, PhD, the Emma Pfeiffer Merner Professor in Medical Sciences and a professor of biochemistry. Researchers can mitigate overactive LRRK2 using MLi-2 LRRK2 kinase inhibitor, a molecule that attaches to the enzyme and decreases its activity.

Pfeffer added that because the genetic mutation is not the only way to end up with overactive LRRK2 enzyme, the inhibitor treatment might help with other types of Parkinson’s disease or even other neurodegenerative diseases.

Pfeffer is the senior author of the study published in Science Signaling on July 1. Ebsy Jaimon, PhD, a postdoctoral scholar in biochemistry, is the lead author. The work is part of a longstanding collaboration with Dario Alessi, PhD, at the University of Dundee in Scotland.

Cellular antennae

About 25% of Parkinson’s disease cases are caused by genetic mutations, and the single genetic mutation that makes the LRRK2 enzyme too active is one of the most common. An overactive LRRK2 enzyme causes cells to lose their primary cilia, a cellular appendage that acts like an antenna, sending and receiving chemical messages. A cell that has lost its primary cilia is like your mobile phone when the network is down — no messages come through or are sent.

In a healthy brain, many messages are sent back and forth between dopamine neurons in a region of the brain called the substantia nigra and the striatum. These cellular “conversations” are possible because dopamine neuron axons, which are tubular extensions coming off the cell body, reach all the way to the striatum to communicate with neurons and glia, cells that support neuronal function.

An important communication that is disrupted by too much LRRK2 enzyme activity occurs when dopamine neurons are stressed and release a signal in the striatum called sonic hedgehog (named after the cartoon character). In a healthy brain, it causes certain neurons and astrocytes, a type of glial support cell, in the striatum to produce proteins called neuroprotective factors. As their name suggests, these proteins help shield other cells from dying. When there is too much LRRK2 enzyme activity, many of the striatal cells lose their primary cilia — and their ability to receive the signal from dopamine neurons. This disruption in sonic hedgehog signaling means that needed neuroprotective factors are not produced.

“Many kinds of processes necessary for cells to survive are regulated through cilia sending and receiving signals. The cells in the striatum that secrete neuroprotective factors in response to hedgehog signals also need hedgehog to survive. We think that when cells have lost their cilia, they are also on the pathway to death because they need cilia to receive signals that keep them alive,” Pfeffer explained.

Restored cilia were unexpected

The goal of the study was to test if the MLi-2 LRRK2 kinase inhibitor reversed the effects of too much LRRK2 enzyme activity. Because the neurons and glia that were examined in this study were fully mature and no longer reproducing through cell division, the researchers were initially unsure whether cilia could regrow. Working with mice with the genetic mutation that causes overactive LRRK2 and symptoms consistent with early Parkinson’s disease, the scientists first tried feeding the mice the inhibitor for two weeks. There were no changes detected in brain structure, signaling or the viability of the dopamine neurons.

Recent findings on neurons involved in regulating circadian rhythms, or sleep-wake cycles, inspired the researchers to try again. The primary cilia on those cells — which were also no longer dividing — grew and shrank every 12 hours.

“The findings that other non-dividing cells grow cilia made us realize that it was theoretically possible for the inhibitor to work,” Pfeffer said.

The team decided to see what happened after mice with overactive LRRK2 enzyme consumed the inhibitor for a longer period of time; Pfeffer described the results as “astounding.”

After three months of eating the inhibitor, the percentage of striatal neurons and glia typically affected by the overactive LRRK2 enzyme that had primary cilia in mice with the genetic mutation was indistinguishable from that in mice without the genetic mutation. In the same way moving from an area with spotty cell service to one with good service restores our ability to send and receive text messages, the increase in primary cilia restored communication between dopamine neurons and the striatum.

The striatal neurons and glia were again secreting neuroprotective factors in response to hedgehog signaling from dopamine neurons in the same amounts as the brains of mice without the genetic mutation. The hedgehog signaling from dopamine neurons decreased, suggesting they were under less stress. And, indicators of the density of dopamine nerve endings within the striatum doubled, suggesting an initial recovery for neurons that had been in the process of dying.

“These findings suggest that it might be possible to improve, not just stabilize, the condition of patients with Parkinson’s disease,” Pfeffer said.

The earliest symptoms of Parkinson’s disease begin about 15 years before someone notices a tremor. Typically, these symptoms are a loss of smell, constipation and a sleep disorder in which people act out their dreams while still sleeping, according to Pfeffer. She said the hope is that people who have the LRRK2 genetic mutation can start a treatment that inhibits the enzyme as early as possible.

The next step for the research team is to test whether other forms of Parkinson’s disease that are not associated with the LRRK2 genetic mutation could benefit from this type of treatment.

“We are so excited about these findings. They suggest this approach has great promise to help patients in terms of restoring neuronal activity in this brain circuit,” Pfeffer said. “There are multiple LRRK2 inhibitor clinical trials underway, and our hope is that these findings in mice will hold true for patients in the future.”

The study was funded by The Michael J. Fox Foundation for Parkinson’s Research, the Aligning Science Across Parkinson’s initiative and the United Kingdom Medical Research Council.

Incoming information from the retina is channeled into two pathways in the brain’s visual system: one that’s responsible for processing color and fine spatial detail, and another that’s involved in spatial localization and detecting high temporal frequencies. A new study from MIT provides an account for how these two pathways may be shaped by developmental factors.

Newborns typically have poor visual acuity and poor color vision because their retinal cone cells are not well-developed at birth. This means that early in life, they are seeing blurry, color-reduced imagery. The MIT team proposes that such blurry, color-limited vision may result in some brain cells specializing in low spatial frequencies and low color tuning, corresponding to the so-called magnocellular system. Later, with improved vision, cells may tune to finer details and richer color, consistent with the other pathway, known as the parvocellular system.

To test their hypothesis, the researchers trained computational models of vision on a trajectory of input similar to what human babies receive early in life – low-quality images early on, followed by full-color, sharper images later. They found that these models developed processing units with receptive fields exhibiting some similarity to the division of magnocellular and parvocellular pathways in the human visual system. Vision models trained on only high-quality images did not develop such distinct characteristics.

The findings potentially suggest a mechanistic account of the emergence of the parvo/magno distinction, which is one of the key organizing principles of the visual pathway in the mammalian brain.”

Pawan Sinha, MIT professor of brain and cognitive sciences and the senior author of the study

MIT postdocs Marin Vogelsang and Lukas Vogelsang are the lead authors of the study, which appears today in the journal Communications Biology. Sidney Diamond, an MIT research affiliate, and Gordon Pipa, a professor of neuroinformatics at the University of Osnabrueck, are also authors of the paper.

Sensory input

The idea that low-quality visual input might be beneficial for development grew out of studies of children who were born blind but later had their sight restored. An effort from Sinha’s laboratory, Project Prakash, has screened and treated thousands of children in India, where reversible forms of vision loss such as cataracts are relatively common. After their sight is restored, many of these children volunteer to participate in studies in which Sinha and his colleagues track their visual development.

In one of these studies, the researchers found that children who had cataracts removed exhibited a marked drop in object-recognition performance when the children were presented with black and white images, compared to colored ones. Those findings led the researchers to hypothesize that reduced color input characteristic of early typical development, far from being a hindrance, allows the brain to learn to recognize objects even in images that have impoverished or shifted colors.

“Denying access to rich color at the outset seems to be a powerful strategy to build in resilience to color changes and make the system more robust against color loss in images,” Sinha says.

In that study, the researchers also found that when computational models of vision were initially trained on grayscale images, followed by color images, their ability to recognize objects was more robust than that of models trained only on color images. Similarly, another study from the lab found that models performed better when they were trained first on blurry images, followed by sharper images.

To build on those findings, the MIT team wanted to explore what might be the consequences of both of those features – color and visual acuity – being limited at the outset of development. They hypothesized that these limitations might contribute to the development of the magnocellular and parvocellular pathways.

In addition to being highly attuned to color, cells in the parvocellular pathway have small receptive fields, meaning that they receive input from more compact clusters of retinal ganglion cells. This helps them to process fine detail. Cells in the magnocellular pathway pool information across larger areas, allowing them to process more global spatial information.

To test their hypothesis that developmental progressions could contribute to the magno and parvo cell selectivities, the researchers trained models on two different sets of images. One model was presented with a standard dataset of images that are used to train models to categorize objects. The other dataset was designed to roughly mimic the input that the human visual system receives from birth. This “biomimetic” data consists of low-resolution, grayscale images in the first half of the training, followed by high-resolution, colorful images in the second half.

After the models were trained, the researchers analyzed the models’ processing units – nodes within the network that bear some resemblance to the clusters of cells that process visual information in the brain. They found that the models trained on the biomimetic data developed a distinct subset of units that are jointly responsive to low-color and low-spatial-frequency inputs, similar to the magnocellular pathway. Additionally, these biomimetic models exhibited groups of more heterogenous parvocellular-like units tuned predominantly to higher spatial frequencies or richer color signals. Such distinction did not emerge in the models trained on full color, high-resolution images from the start.

“This provides some support for the idea that the ‘correlation’ we see in the biological system could be a consequence of the types of inputs that are available at the same time in normal development,” Lukas Vogelsang says.

Object recognition

The researchers also performed additional tests to reveal what strategies the differently trained models were using for object recognition tasks. In one, they asked the models to categorize images of objects where the shape and texture did not match – for example, an animal with the shape of cat but the texture of an elephant.

This is a technique several researchers in the field have employed to determine which image attributes a model is using to categorize objects: the overall shape or the fine-grained textures. The MIT team found that models trained on biomimetic input were markedly more likely to use an object’s shape to make those decisions, just as humans usually do. Moreover, when the researchers systematically removed the magnocellular-like units from the models, the models quickly lost their tendency to use shape to make categorizations.

In another set of experiments, the researchers trained the models on videos instead of images, which introduces a temporal dimension. In addition to low spatial resolution and color sensitivity, the magnocellular pathway responds to high temporal frequencies, allowing it to quickly detect changes in the position of an object. When models were trained on biomimetic video input, the units most tuned to high temporal frequencies were indeed the ones that also exhibited magnocellular-like properties in the spatial domain.

Overall, the results support the idea that low-quality sensory input early in life may contribute to the organization of sensory processing pathways of the brain, the researchers say. The findings do not rule out innate specification of the magno and parvo pathways, but provide a proof of principle that visual experience over the course of development could also play a role.

“The general theme that seems to be emerging is that the developmental progression that we go through is very carefully structured in order to give us certain kinds of perceptual proficiencies, and it may also have consequences in terms of the very organization of the brain,” Sinha says.

The research was funded by the National Institutes of Health, the Simons Center for the Social Brain, the Japan Society for the Promotion of Science, and the Yamada Science Foundation.