Proteins do not misbehave and misfold out of the blue. There is a delicate ecosystem of biochemical interactions and environments that usually let them twist, unfold, refold and do their jobs as they’re meant to.

However, as researchers from Michigan Technological University explore in an article published in ACS Chemical Neuroscience, even a small change may cause long-term consequences.

For amyloid beta peptides — considered a major hallmark of Alzheimer’s disease — a common chemical modification at a particular location on the molecule has a butterfly effect that leads to protein misfolding, aggregation and cellular toxicity.

Ashutosh Tiwari, associate professor of chemistry at Michigan Tech, explains that misfolded amyloid beta proteins tend to pile up and form aggregates, which can form stringy fibrils or balled-up amorphous shapes.

To understand what causes the different shapes and to assess their toxicity, Tiwari’s team looked at acetylation.

Acetylation is one of the most common chemical modifications proteins undergo, but one of the least researched in terms of how it affects amyloid beta toxicity. On amyloid beta proteins, acetylation can occur at two sites: lysine 16 and lysine 28.

The team found that acetylation at lysine 16 led to the disordered aggregates that formed sticky but flexible amorphous structures and showed high levels of toxicity. They also found the aggregates showed higher free radical formation.

“No one has done a systematic study to show if you acetylate amyloid beta it changes how the aggregate looks, then it changes its biophysical properties and hence toxicity,” Tiwari said. “What we’re saying is that the shape, stickiness and flexibility of the aggregated protein structure can play a vital role in the cellular toxicity and may also affect the mechanism of toxicity.”

In Alzheimer’s, these aggregates accumulate in the part of the brain that affects memory. It’s a disease that the Alzheimer’s Organization reports is the sixth leading cause of death in the US and will cost the nation about $305 billion in 2020. Tiwari says what we truly need to understand about the disease is that there is no single cause, no single trigger, and probably no silver bullet because of the chemistry involved.

“This is how a subtle change on a single position can affect a whole protein’s aggregation,” Tiwari said, adding that the effect of acetylation on tau, another protein aggregation, has been far more studied than amyloid beta. Also, many researchers still think a misfolded protein has to look a certain way to become problematic, and that other misfolded forms are less of an issue.

Tiwari agrees some of the proteins’ changes are subtle, and compares discerning the differences and their effects to snow tires. Snow tires have deeper treads and a more flexible material to handle winter roads, but it’s hard to point out those features at highway speeds. Like different kinds of tires, protein shapes can appear indistinguishable at a distance.

“This is not something that can be viewed from afar — it’s a touch-and-feel property,” Tiwari said. “We have to interrogate these properties. We have to look at these structures more deeply from both morphology and biophysical perspectives.”

When we do, we may better understand the complexity of the misfolded proteins and amyloid beta toxicity that can cause neurodegenerative diseases like Alzheimer’s.

Increasing aridity is already a clear trend across the western United States, where anthropogenic climate warming is contributing to declining river flows, drier soils, widespread tree death, stressed agricultural crops, catastrophic wildfires and protracted droughts, according to the authors of a Commentary article published online May 19 in Proceedings of the National Academy of Sciences.

At the same time, human-caused warming is also driving increased aridity eastward across North America, with no end in sight, according to climate scientists Jonathan Overpeck of the University of Michigan and Bradley Udall of Colorado State University.

“The impact of warming on the West’s river flows, soils, and forests is now unequivocal,” write Overpeck, dean of the U-M School for Environment and Sustainability, and Udall, senior water and climate scientist at Colorado State. “There is a clear longer-term trend toward greater aridification, a trend that only climate action can stop.”

The Commentary article responds to a PNAS paper, published May 11 by Justin Martin of the U.S. Geological Survey and his colleagues, that showed how warming is causing streamflow declines in the northern Rocky Mountains, including the nation’s largest river basin, the Missouri.

The Martin et al. study used tree-ring records to analyze the 2000-2010 Upper Missouri River Basin drought and concluded that “recent warming aligns with increasing drought severities that rival or exceed any estimated over the last 12 centuries.”

The study details the mechanisms of temperature-driven streamflow declines, and it “places more focus on how anthropogenic climate warming is progressively increasing the risk of hot drought and more arid conditions across an expanding swath of the United States,” according to Overpeck and Udall.

The Martin et al. study also highlights the way temperature-driven aridity in the West is typically framed in terms of episodic drought. Many water and land managers, as well as the general public, implicitly assume that when returning rains and snowfall break a long drought, arid conditions will also fade away.

But that’s a faulty assumption, one that ignores mounting evidence all around us, according to Overpeck and Udall.

“Anthropogenic climate change calls this assumption into question because we now know with high confidence that continued emissions of greenhouse gases into the atmosphere guarantees continued warming, and that this continued warming makes more widespread, prolonged and severe dry spells and droughts almost a sure bet,” they write. “Greater aridity is redefining the West in many ways, and the costs to human and natural systems will only increase as we let the warming continue.”

Anticipated impacts in the Upper Missouri River Basin mirror changes already occurring in the Southwest, where the trend toward warming-driven aridification is clearest.

Rivers in the Southwest provide the only large, sustainable water supply to more than 40 million people, yet flows have declined significantly since the late 20th century. Declining flows in the region’s two most important rivers, the Colorado and the Rio Grande, have been attributed in part to increasing temperatures caused by human activities, most notably the burning of fossil fuels.

Multiple processes tied to warming are likely implicated in the observed aridification of the West, according to Overpeck and Udall. For starters, warmer air can hold more water vapor, and this thirsty air draws moisture from water bodies and land surfaces through evaporation and evapotranspiration — further drying soils, stressing plants and reducing streamflow.

But the atmosphere’s increased capacity to hold water vapor also boosts the potential for precipitation; rain and snow amounts are, in fact, rising in many regions of the United States outside the Southwest. However, the frequency and intensity of dry spells and droughts are expected to increase across much of the continent in coming decades, even if average annual precipitation levels rise, according to Overpeck and Udall.

“Perhaps most troubling is the growing co-occurrence of hot and dry summer conditions, and the likely expansion, absent climate change action, of these hot-dry extremes all the way to the East Coast of North America, north deep into Canada, and south into Mexico,” they write.

“Other parts of North America likely won’t see the widespread aridification and decadal to multi-decadal droughts of the West, but will nonetheless continue to see more frequent and severe arid events — extreme dry spells, flash droughts and interannual droughts will become part of the new normal,” according to Overpeck and Udall.

“Unfortunately, climate change and this aridification are likely irreversible on human time scales, so the sooner emissions of greenhouse gases to the atmosphere are halted, the sooner the aridification of North America will stop getting worse.”

Weaving this story, element by element, from roughly 140 million miles (225 million kilometers) away is a painstaking process. But scientists aren’t the type to be easily deterred. Orbiters and rovers at Mars have confirmed that the planet once had liquid water, thanks to clues that include dry riverbeds, ancient shorelines, and salty surface chemistry. Using NASA’s Curiosity Rover, scientists have found evidence for long-lived lakes. They’ve also dug up organic compounds, or life’s chemical building blocks. The combination of liquid water and organic compounds compels scientists to keep searching Mars for signs of past — or present — life.

Despite the tantalizing evidence found so far, scientists’ understanding of Martian history is still unfolding, with several major questions open for debate. For one, was the ancient Martian atmosphere thick enough to keep the planet warm, and thus wet, for the amount of time necessary to sprout and nurture life? And the organic compounds: are they signs of life — or of chemistry that happens when Martian rocks interact with water and sunlight?

In a recent Nature Astronomy report on a multi-year experiment conducted in the chemistry lab inside Curiosity’s belly, called Sample Analysis at Mars (SAM), a team of scientists offers some insights to help answer these questions. The team found that certain minerals in rocks at Gale Crater may have formed in an ice-covered lake. These minerals may have formed during a cold stage sandwiched between warmer periods, or after Mars lost most of its atmosphere and began to turn permanently cold.

Gale is a crater the size of Connecticut and Rhode Island combined. It was selected as Curiosity’s 2012 landing site because it had signs of past water, including clay minerals that might help trap and preserve ancient organic molecules. Indeed, while exploring the base of a mountain in the center of the crater, called Mount Sharp, Curiosity found a layer of sediments 1,000 feet (304 meters) thick that was deposited as mud in ancient lakes. To form that much sediment an incredible amount of water would have flowed down into those lakes for millions to tens of millions of warm and humid years, some scientists say. But some geological features in the crater also hint at a past that included cold, icy conditions.

“At some point, Mars’ surface environment must have experienced a transition from being warm and humid to being cold and dry, as it is now, but exactly when and how that occurred is still a mystery,” says Heather Franz, a NASA geochemist based at NASA’s Goddard Space Flight Center in Greenbelt, Maryland.

Franz, who led the SAM study, notes that factors such as changes in Mars’ obliquity and the amount of volcanic activity could have caused the Martian climate to alternate between warm and cold over time. This idea is supported by chemical and mineralogical changes in Martian rocks showing that some layers formed in colder environments and others formed in warmer ones.

In any case, says Franz, the array of data collected by Curiosity so far suggests that the team is seeing evidence for Martian climate change recorded in rocks.

Carbon and oxygen star in the Martian climate story

Franz’s team found evidence for a cold ancient environment after the SAM lab extracted the gases carbon dioxide, or CO₂, and oxygen from 13 dust and rock samples. Curiosity collected these samples over the course of five Earth years (Earth years vs. Mars years).

CO₂ is a molecule of one carbon atom bonded with two oxygen atoms, with carbon serving as a key witness in the case of the mysterious Martian climate. In fact, this simple yet versatile element is as critical as water in the search for life elsewhere. On Earth, carbon flows continuously through the air, water, and surface in a well-understood cycle that hinges on life. For example, plants absorb carbon from the atmosphere in the form of CO₂. In return, they produce oxygen, which humans and most other life forms use for respiration in a process that ends with the release of carbon back into the air, again via CO₂, or into the Earth’s crust as life forms die and are buried.

Scientists are finding there’s also a carbon cycle on Mars and they’re working to understand it. With little water or abundant surface life on the Red Planet for at least the past 3 billion years, the carbon cycle is much different than Earth’s.

“Nevertheless, the carbon cycling is still happening and is still important because it’s not only helping reveal information about Mars’ ancient climate,” says Paul Mahaffy, principal investigator on SAM and director of the Solar System Exploration Division at NASA Goddard. “It’s also showing us that Mars is a dynamic planet that’s circulating elements that are the buildings blocks of life as we know it.”

The gases build a case for a chilly period

After Curiosity fed rock and dust samples into SAM, the lab heated each one to nearly 1,650 degrees Fahrenheit (900 degrees Celsius) to liberate the gases inside. By looking at the oven temperatures that released the CO₂ and oxygen, scientists could tell what kind of minerals the gases were coming from. This type of information helps them understand how carbon is cycling on Mars.

Various studies have suggested that Mars’ ancient atmosphere, containing mostly CO₂, may have been thicker than Earth’s is today. Most of it has been lost to space, but some may be stored in rocks at the planet’s surface, particularly in the form of carbonates, which are minerals made of carbon and oxygen. On Earth, carbonates are produced when CO₂ from the air is absorbed in the oceans and other bodies of water and then mineralized into rocks. Scientists think the same process happened on Mars and that it could help explain what happened to some of the Martian atmosphere.

Yet, missions to Mars haven’t found enough carbonates in the surface to support a thick atmosphere.

Nonetheless, the few carbonates that SAM did detect revealed something interesting about the Martian climate through the isotopes of carbon and oxygen stored in them. Isotopes are versions of each element that have different masses. Because different chemical processes, from rock formation to biological activity, use these isotopes in different proportions, the ratios of heavy to light isotopes in a rock provide scientists with clues to how the rock formed.

In some of the carbonates SAM found, scientists noticed that the oxygen isotopes were lighter than those in the Martian atmosphere. This suggests that the carbonates did not form long ago simply from atmospheric CO₂ absorbed into a lake. If they had, the oxygen isotopes in the rocks would have been slightly heavier than the ones in the air.

While it’s possible that the carbonates formed very early in Mars’ history, when the atmospheric composition was a bit different than it is today, Franz and her colleagues suggest that the carbonates more likely formed in a freezing lake. In this scenario, the ice could have sucked up heavy oxygen isotopes and left the lightest ones to form carbonates later. Other Curiosity scientists have also presented evidence suggesting that ice-covered lakes could have existed in Gale Crater.

So where is all the carbon?

The low abundance of carbonates on Mars is puzzling, scientists say. If there aren’t many of these minerals at Gale Crater, perhaps the early atmosphere was thinner than predicted. Or maybe something else is storing the missing atmospheric carbon.

Based on their analysis, Franz and her colleagues suggest that some carbon could be sequestered in other minerals, such as oxalates, which store carbon and oxygen in a different structure than carbonates. Their hypothesis is based on the temperatures at which CO₂ was released from some samples inside SAM — too low for carbonates, but just right for oxalates — and on the different carbon and oxygen isotope ratios than the scientists saw in the carbonates.

A model of a carbonate molecule next to an oxalate molecule

Oxalates are the most common type of organic mineral produced by plants on Earth. But oxalates also can be produced without biology. One way is through the interaction of atmospheric CO₂ with surface minerals, water, and sunlight, in a process known as abiotic photosynthesis. This type of chemistry is hard to find on Earth because there’s abundant life here, but Franz’s team hopes to create abiotic photosynthesis in the lab to figure out if it actually could be responsible for the carbon chemistry they’re seeing in Gale Crater.

On Earth, abiotic photosynthesis may have paved the way for photosynthesis among some of the first microscopic life forms, which is why finding it on other planets interests astrobiologists.

Even if it turns out that abiotic photosynthesis locked some carbon from the atmosphere into rocks at Gale Crater, Franz and her colleagues would like to study soil and dust from different parts of Mars to understand if their results from Gale Crater reflect a global picture. They may one day get a chance to do so. NASA’s Perseverance Mars rover, due to launch to Mars between July and August 2020, plans to pack up samples in Jezero Crater for possible return to labs on Earth.