But many researchers believe that the neurodegenerative disorder may get started far away from the brain — in the gut — and years before the first neurological signs appear.

New findings by Columbia researchers David Sulzer, PhD, and Dritan Agalliu, PhD, and two of their graduate students are adding to evidence backing this hypothesis — and showing that what triggers initial gastrointestinal changes in Parkinson’s could be a misdirected immune attack.

“If this is the beginning of Parkinson’s in many people, we could potentially identify who has the disease before it ever reaches the brain and hopefully stop it in its tracks,” Sulzer says. The new findings were published Aug. 18 in Neuron.

Autoimmunity and the gut

The gut-first theory of Parkinson’s, originally proposed 20 years ago, started to intrigue Sulzer after his own research pointed toward the role of an autoimmune response in Parkinson’s.

In Parkinson’s, a protein called alpha-synuclein becomes misfolded, accumulates inside neurons, and slowly poisons the cells. Sulzer’s lab in collaboration with immunologists at the La Jolla Institute of Immunology has shown that small portions of the misfolded alpha-synuclein also can appear on the outside of neurons, which makes the neurons vulnerable to attack from the immune system. The immune attack could be doing more acute damage to the neurons than the internal deposits of alpha synuclein.

“The blood of Parkinson’s patients often contains immune cells that are primed to attack the neurons,” Sulzer says, “but it’s not clear where or when they are primed.”

The gut was an intriguing possibility because it contains the same neurons and because most Parkinson’s patients experience constipation years before brain symptoms emerge and the disease is diagnosed. To pursue this hypothesis, Sulzer teamed up with Agalliu, a neuroimmunologist with expertise in mouse models of another neurological disorder (multiple sclerosis) that has autoimmune features.

Immune response to alpha synuclein leads to gut symptoms

To find out if an immune reaction to alpha-synuclein can kick-start the disease and where, Francesca Garretti and Connor Monahan, grad students directed by Agalliu and Sulzer, first created a mouse capable of displaying pieces of misfolded alpha-synuclein on cell surfaces (natural mice do not have this ability). They then injected the mice with alpha-synuclein and monitored what happened in the brain and the gut.

The researchers did not see any signs resembling Parkinson’s disease in the brain, but they did see that an immune attack on neurons in the gut produced constipation and other gastrointestinal effects resembling those seen in most Parkinson’s patients years before they are diagnosed with the disease.

“This shows that an autoimmune reaction can lead to what appears to be the early stages of Parkinson’s and is strong support that Parkinson’s is in part an autoimmune disease,” Sulzer says.

The findings also raise the possibility that early detection — and then interruption — of an immune response in the gut could prevent a later attack on the brain’s neurons and stop Parkinson’s in its tracks.

Wanted: A mouse with Parkinson’s disease

Right now, though, it’s not clear how big a role the immune system plays in the Parkinson’s brain. The answer to that question may become clearer if the researchers find out why the brains of their mice did not develop any signs of Parkinson’s.

The team hypothesizes that the immune cells in their mouse model may not be reaching the brain because the animals are young and age has not yet weakened the blood-brain barrier sufficiently to let immune cells squeeze through. Opening the barrier or accelerating the aging process may lead to mice that develop gastrointestinal and brain symptoms.

“Our ultimate goal is to develop a model of Parkinson’s disease in mice that recreates the human disease process, which doesn’t exist right now,” Sulzer says. “That will be critical in answering questions about the disease that we can’t explore in people and eventually developing better therapies.”

Inspired by bones and other cellular solids found in nature, humans have used the same concept to develop architected materials. By changing the geometry of the unit cells that make up these materials, researchers can customize the material’s mechanical, thermal, or acoustic properties. Architected materials are used in many applications, from shock-absorbing packing foam to heat-regulating radiators.

Using kirigami, the ancient Japanese art of folding and cutting paper, MIT researchers have now manufactured a type of high-performance architected material known as a plate lattice, on a much larger scale than scientists have previously been able to achieve by additive fabrication. This technique allows them to create these structures from metal or other materials with custom shapes and specifically tailored mechanical properties.

“This material is like steel cork. It is lighter than cork, but with high strength and high stiffness,” says Professor Neil Gershenfeld, who leads the Center for Bits and Atoms (CBA) at MIT and is senior author of a new paper on this approach.

The researchers developed a modular construction process in which many smaller components are formed, folded, and assembled into 3D shapes. Using this method, they fabricated ultralight and ultrastrong structures and robots that, under a specified load, can morph and hold their shape.

Because these structures are lightweight but strong, stiff, and relatively easy to mass-produce at larger scales, they could be especially useful in architectural, airplane, automotive, or aerospace components.

Joining Gershenfeld on the paper are co-lead authors Alfonso Parra Rubio, a research assistant in the CBA, and Klara Mundilova, an MIT electrical engineering and computer science graduate student; along with David Preiss, a graduate student in the CBA; and Erik D. Demaine, an MIT professor of computer science. The research will be presented at ASME’s Computers and Information in Engineering Conference.

Fabricating by folding

Architected materials, like lattices, are often used as cores for a type of composite material known as a sandwich structure. To envision a sandwich structure, think of an airplane wing, where a series of intersecting, diagonal beams form a lattice core that is sandwiched between a top and bottom panel. This truss lattice has high stiffness and strength, yet is very lightweight.

Plate lattices are cellular structures made from three-dimensional intersections of plates, rather than beams. These high-performance structures are even stronger and stiffer than truss lattices, but their complex shape makes them challenging to fabricate using common techniques like 3D printing, especially for large-scale engineering applications.

The MIT researchers overcame these manufacturing challenges using kirigami, a technique for making 3D shapes by folding and cutting paper that traces its history to Japanese artists in the 7th century.

Kirigami has been used to produce plate lattices from partially folded zigzag creases. But to make a sandwich structure, one must attach flat plates to the top and bottom of this corrugated core onto the narrow points formed by the zigzag creases. This often requires strong adhesives or welding techniques that can make assembly slow, costly, and challenging to scale.

The MIT researchers modified a common origami crease pattern, known as a Miura-ori pattern, so the sharp points of the corrugated structure are transformed into facets. The facets, like those on a diamond, provide flat surfaces to which the plates can be attached more easily, with bolts or rivets.

“Plate lattices outperform beam lattices in strength and stiffness while maintaining the same weight and internal structure,” says Parra Rubio. “Reaching the H-S upper bound for theoretical stiffness and strength has been demonstrated through nanoscale production using two-photon lithography. Plate lattices construction has been so difficult that there has been little research on the macro scale. We think folding is a path to easier utilization of this type of plate structure made from metals.”

Customizable properties

Moreover, the way the researchers design, fold, and cut the pattern enables them to tune certain mechanical properties, such as stiffness, strength, and flexural modulus (the tendency of a material to resist bending). They encode this information, as well as the 3D shape, into a creasing map that is used to create these kirigami corrugations.

For instance, based on the way the folds are designed, some cells can be shaped so they hold their shape when compressed while others can be modified so they bend. In this way, the researchers can precisely control how different areas of the structure will deform when compressed.

Because the flexibility of the structure can be controlled, these corrugations could be used in robots or other dynamic applications with parts that move, twist, and bend.

To craft larger structures like robots, the researchers introduced a modular assembly process. They mass produce smaller crease patterns and assemble them into ultralight and ultrastrong 3D structures. Smaller structures have fewer creases, which simplifies the manufacturing process.

Using the adapted Miura-ori pattern, the researchers create a crease pattern that will yield their desired shape and structural properties. Then they utilize a unique machine — a Zund cutting table — to score a flat, metal panel that they fold into the 3D shape.

“To make things like cars and airplanes, a huge investment goes into tooling. This manufacturing process is without tooling, like 3D printing. But unlike 3D printing, our process can set the limit for record material properties,” Gershenfeld says.

Using their method, they produced aluminum structures with a compression strength of more than 62 kilonewtons, but a weight of only 90 kilograms per square meter. (Cork weighs about 100 kilograms per square meter.) Their structures were so strong they could withstand three times as much force as a typical aluminum corrugation.

The versatile technique could be used for many materials, such as steel and composites, making it well-suited for the production lightweight, shock-absorbing components for airplanes, automobiles, or spacecraft.

However, the researchers found that their method can be difficult to model. So, in the future, they plan to develop user-friendly CAD design tools for these kirigami plate lattice structures. In addition, they want to explore methods to reduce the computational costs of simulating a design that yields desired properties.

Parra Rubio, Mundilova and other MIT graduate students also used this technique to create three large-scale, folded artworks from aluminum composite that are on display at the MIT Media Lab. Despite the fact that each artwork is several meters in length, the structures only took a few hours to fabricate.

“At the end of the day, the artistic piece is only possible because of the math and engineering contributions we are showing in our papers. But we don’t want to ignore the aesthetic power of our work,” Parra Rubio says.

This work was funded, in part, by the Center for Bits and Atoms Research Consortia, an AAUW International Fellowship, and a GWI Fay Weber Grant.