This past October, UC Berkeley’s Helen Wills Neuroscience Institute (HWNI) held its annual retreat. Gathered within Cal’s football stadium, professors and students from across the institute presented novel research developments and future directions. However, the most striking feature of the gathering wasn’t the research being presented per se. It was the sheer breadth of science present. Cognitive scientists rubbed shoulders with cell biologists and systems neuroscientists alike, all in the same intellectual space. It was a refreshing sight, and a far cry from the archetypal academic environment where researchers are often found publishing and presenting only within their specialized fields.
Neuroscience research increasingly necessitates approaches from multiple sub-disciplines. Any one approach alone would likely fail to capture the complexity of a given neural phenomenon. Take memory, for example. At the broadest level, cognitive neuroscientists assess memory by measuring activity in specialized regions of the brain and monitoring how a subject’s memory may be perturbed under certain conditions. On a deeper level, systems neuroscientists disentangle how neurons wire together to process information and yield memory formation and recall. Deeper still, cellular and molecular neuroscientists probe how the individual neurons that make up the neural circuits of memory develop and function. Importantly, it's only when all three domains are considered together that such an immensely complicated concept as memory can be comprehensively understood.
Within UC Berkeley’s cross-departmental HWNI, discoveries in and across cognitive, systems, and cellular and molecular neuroscience are being made in pursuit of understanding a devastating set of pathologies: neurodegeneration. Neurodegeneration encompasses a group of diseases—including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis—characterized by neuronal death and loss of neural functions such as memory, cognition, sensory perception, and motor abilities. An estimated 6.5 million Americans over the age of 65 are living with Alzheimer’s disease alone. Furthermore, neurodegeneration poses an increasingly significant public health burden over the next few generations, as increased age represents the largest risk factor for neurodegeneration and the aged demographic is growing rapidly worldwide (it is estimated that a fifth of Americans will be over the age of 65 by the year 2030). Unfortunately, however, the field’s understanding of these diseases and their causes are incomplete and current treatments to address them remain limited. To tackle these questions, researchers at UC Berkeley are leveraging neuroscience’s multidisciplinary nature and investigating these diseases across sub-disciplines.
A molecular perspective: halting neurodegenerative protein aggregation
Starting at a microscopic scale, investigators are trying to understand the cellular and molecular drivers of neurodegeneration. In neurodegenerative disease, neurons and other cell types of the brain become damaged and eventually die when normal cellular processes go awry. Neurodegeneration demonstrates a variety of pathological features, from dysfunction in organelles (such as the energy-producing mitochondria and the waste-disposing lysosomes) to immune activation and cellular stress. However, of all the cellular features of neurodegeneration, one is considered a key hallmark of neurodegenerative disease: protein aggregation. These aggregates take shape when specific proteins in neurons are misfolded and clump together. Nearly every neurodegenerative disease, from Alzheimer’s to Huntington’s, involves the formation of protein aggregates, though each disease involves a different protein or set of proteins. What gives rise to these aggregates and to what extent they drive disease progression is still an area of active research, but their correlation with neuronal dysfunction is well established. The Rapé lab, led by Professor Michael Rapé of UC Berkeley’s HWNI and Department of Molecular and Cell Biology, is taking a unique approach to studying how these protein aggregates initially emerge in a cell.
Rapé broadly describes his lab’s research as working to “understand the signaling pathways that allow cells to either obtain a particular fate or preserve it.” To preserve a homeostatic, or stable and functional, cellular state, cells employ a series of quality control systems which act as internal self-regulating mechanisms. One focus of the Rapé lab is how ubiquitin, a cellular tag that marks proteins for degradation, plays a role in maintaining protein homeostasis. It was through investigating this quality control system that the Rapé lab serendipitously uncovered a connection to neurodegeneration. “Starting with a discovery by a graduate student that there are specific [ubiquitin] chains that are better signals for degradation,” Rapé explains, “we see that there are different tiers of quality control. Some are really, really powerful and they are focused on the aggregation-prone proteins.”
It was this connection between quality control systems and protein aggregation that prompted the lab’s foray into neurodegeneration. The lab began studying how specific E3 ligases, the class of enzymes that tag proteins with ubiquitin, mediate degradation of proteins that are susceptible to aggregation in neurodegeneration, and how mutations in these enzymes may be implicated in pathology. “The more we move into the quality control field, the more we come upon neurodegenerative diseases and discover enzymes that are mutated in neurodegenerative diseases,” Rapé affirms.
Using E3 ligase-mediated degradation as a foundation, the Rapé lab has begun exploring how cells degrade a variety of protein aggregates implicated in numerous neurodegenerative diseases. This work represents neurodegenerative research at a deep, molecular level. Rapé shared how he envisions this work translating into therapies that could combat decline in human cognition and memory, functions that extend far past the cellular level. “If you want to focus on either small molecule strategies or even gene-editing strategies, I think you need to have a very clear understanding of the molecular machinery.” Rapé elaborates, “For us, that’s always been a driving force. We want to understand how it works, we want to solve the structures, we want to do all these things. Then we already have an extremely good starting point to go to the next step, which is how can we manipulate it in treating disease.” Through researching protein aggregates as they form, the Rapé lab’s work illustrates how the molecular features of a degenerating neuron can be picked apart to both better understand the basic cellular machinery involved and to synthesize novel approaches for treatment.
Aggregating proteins, however, represent just one step in a cascade of cellular events taking place inside a degenerating neuron, each of which has the potential to be therapeutically targeted. This broad assortment of diseased cellular processes is mirrored by the range of molecular neurodegeneration studied within UC Berkeley’s Department of Molecular and Cell Biology. For example, the Bateup, Hockemeyer, and Rio labs are collaborating to investigate how different gene variants are implicated in Parkinson’s disease using human brain organoid models. The Olzmann lab is identifying mediators of ferroptosis, a newly defined form of cell death implicated in numerous neurodegenerative diseases. The Hurley lab is probing how the lysosome can stop the spread and aggregation of pathological proteins in neurodegeneration. Additionally, the Hurley and Park labs are collaborating to better understand how lysosomes can relieve the problems caused by mitochondrial dysfunction in Parkinson’s disease. The Dillin lab is investigating how maintenance of the proteome, or the set of proteins expressed by a cell, declines in aging and neurodegeneration. And the Schekman lab is investigating the mechanisms through which alpha-synuclein, the protein aggregate implicated in Parkinson's Disease, is unconventionally secreted from neurons and spreads throughout the brain. Ultimately, whether it's through stopping protein aggregation or preventing ferroptosis, researching the molecular mechanisms underlying neurodegeneration allows for a better understanding of what could be driving the pathology and paves the way for therapeutic interventions to treat these diseases at the cellular level.
A systems perspective: using dopamine targets to treat Parkinson’s disease
In parallel with research on a molecular scale, systems neuroscientists have a different perspective on neurodegenerative research. Their work seeks to understand the neural circuits that process the activity of individual neurons and transform them into behaviors. One approach to neurodegenerative research within this sub-discipline is that of the Dan lab, led by Yang Dan of the HWNI and the Department of Molecular and Cell Biology, which studies the neural circuits that mediate sleep and how those circuits are perturbed in Parkinson’s disease. Another approach involves investigating a neural circuit by zooming in on the dynamics of neurotransmitters, the chemical signals passed between neurons. The Isacoff lab, led by Ehud Isacoff, who is also a professor in the HWNI and the Department of Molecular and Cell Biology, is probing how one such neurotransmitter—dopamine—functions in the specific neural circuits that mediate motor movement.
Although popularized as the “feel-good” chemical, dopamine plays a role in far more than just mood. It has a hand in movement, pain sensations, and bodily functions such as heart rate and blood vessel changes. “Dopamine, which is key, functions in just so many aspects of brain behavior,” Isacoff explains. “Whether you’re trying to dissect the functions of a circuit and understand what dopamine is doing, or you’re trying to understand the mechanism of pathology, or you’re trying to develop a treatment for the pathology, in all cases you’re confounded by the multifarious nature of dopamine signaling.” In this way, dopamine research poses a catch-22: dopamine’s broad range of functions highlights the need for a more detailed understanding of its role in specific contexts; however, trying to achieve a more detailed understanding is often confounded by how widespread its signaling is.
To overcome the challenges inherent to dopamine research, the Isacoff lab has developed a set of molecular tools to activate or block, in a timed manner, specific dopamine receptors in specific cells and brain regions. These tools build off optogenetics, a branch of neuroscience in which one can control the firing of neurons with light. This is commonly accomplished through artificially expressing a naturally light-activated channel, which was originally found in microbes, in a specific class of neurons. Shining a pulse of light over the brain opens these channels and induces those neurons to fire. The Isacoff Lab, in collaboration with UC Berkeley’s Kramer lab and the Trauner lab (now at New York University), has instead focused on artificially activating the endogenous channels of the brain. They have developed chemical optogenetics in which the native signaling proteins of the nervous system are made sensitive to light, thereby gaining optical control over the physiological channels that control neural firing. In the past few months, the Isacoff lab reported the first photo-agonist (an optically controlled chemical that activates a receptor) for a specific subset of dopamine receptors, which can be targeted to one cell type in a circuit of the brain that controls movement. Activating these engineered agonists with light effectively simulates the natural signaling that occurs when dopamine is released onto those neurons. Overall, these photoswitchable dopamine agonists allow for a robust and highly controlled method for studying dopaminergic action by zooming in on dopamine’s neuronal targets.
This technology becomes particularly relevant when trying to research Parkinson’s disease. Parkinson’s disease is characterized by the death of dopaminergic neurons that originate in a deep structure of the brain called the substantia nigra and then project out, releasing dopamine to other regions of the brain. Loss of dopamine signaling in Parkinson’s disease causes problems with motor functions, with patients suffering from tremors, slowed movement, and stiffness, among other symptoms. Current treatments for Parkinson’s disease focus on increasing dopamine levels indiscriminately in the brain. In contrast, the work of the Isacoff lab is oriented towards future treatments that can replace dopamine signaling to the neurons that have lost it, when they need it.
The connection to neurodegeneration is an exciting prospect for the Isacoff lab. “So far we have seen that our dopamine agonists can induce movement initiation in healthy animals. The next step is to test whether this also works in the Parkinson’s models,” Isacoff explains. This work would yield therapies that differ from treatments that try to prevent the death of the dopaminergic neurons. Instead, this systems-level research asks: where and how do the neurons that die interact with other neurons, and how can this interaction be compensated for? “This is a different approach. This is a prosthetic approach that’s meant to correct for the loss, not prevent the loss,” Isacoff affirms. Nonetheless, both strategies have the potential to improve lives and contribute to a more comprehensive understanding of neurodegenerative disease.
A cognitive perspective: tying cognitive decline to amyloid and tau in Alzheimer’s patients
Molecular and systems neuroscience affords us a mechanistic understanding of neurodegenerative pathology on cellular and subcellular scales; however, a more global analysis of neuropathology, and one done with human subjects, is where the strengths of cognitive neuroscience lie. Generally, cognitive neuroscience seeks to understand how the brain mediates behavior in a broad sense and where in the brain different information is processed. The Jagust lab, led by William Jagust of UC Berkeley’s HWNI and School of Public Health, uses brain imaging technologies to address these questions in the context of aging and Alzheimer’s disease. “We’re interested in how the brain produces behavior,” Jagust explains, “and we’re interested in how systems in the brain interact with pathology to produce abnormal behavior.” The Jagust lab uses PET scanning to identify the location and concentration of certain pathological proteins in the brain. “We have the tools to, on the one hand, look at cognition and take it apart in various ways, and on the other hand, we have the tools to look at pathology in a living human,” Jagust explains.
A driving force of the Jagust lab’s research is to understand the relationship between the presence of protein aggregates and cognitive decline in Alzheimer’s disease. A hallmark of Alzheimer’s disease pathology is aggregation of the proteins beta-amyloid, which form plaques, and tau, which form neurofibrillary tangles. In the early days of this research, scientists only had the tools to visualize beta-amyloid in the brain, which led to a very unclear relationship between protein aggregates and cognitive dysfunction. “The first studies that came out showed no relationship between where the amyloid is in the brain and the kinds of cognitive loss a person had. In fact, there was an extremely weak relationship. In general, you could have quite a lot of amyloid in your brain and be cognitively normal,” Jagust says.
However, when the tools to measure tau in the brain were developed, things began to click. “When we started to be able to visualize tau, we got a very different picture,” Jagust explains. “The amount of tau in the brain is very correlated with how cognitively impaired you are and also with the type of cognitive impairment you have. There’s also a relationship between the amount of amyloid in the brain and the amount of tau in the brain.” These findings led to a new hypothesis connecting these two types of protein aggregates and cognitive decline. “What we think is happening is that amyloid is driving the tau and that tau is driving the cognitive dysfunction,” says Jagust. Other work has substantiated this idea by correlating the location of tau in the brain and specific forms of cognitive impairment. To this end, Jagust explains how Alzheimer’s disease patients with visual and spatial disorders, for example, have an increased concentration of tau in the occipital cortex, the region of the brain largely responsible for visual processing.
Establishing this kind of framework to describe the basic relationship between the presence of pathological protein aggregates and cognitive decline in humans has been fundamental to the field. This work has informed research on both how therapeutic modalities should target these proteins when trying to treat Alzheimer’s disease as well as what molecular mechanisms could explain this disease progression in humans. To this later point, the Jagust lab has an ongoing collaboration with the Kaufer lab, led by Daniela Kaufer of UC Berkeley’s HWNI and Department of Integrative Biology, that seeks to uncover some of the underlying factors driving beta-amyloid deposition in aging individuals. Specifically, this collaboration investigates the relationship between the spread of beta-amyloid and blood-brain barrier deterioration. The blood-brain barrier constitutes the specialized blood vessels that prevent most molecules and cells from entering the brain as readily as they would in other organs. It gives the brain an extra layer of protection against pathogens or other potential threats. Previous studies from the Kaufer lab and others have demonstrated that this barrier gradually breaks down as one ages. Additionally, the Jagust lab, among others, have shown that amyloid deposition in the brain increases with age. Therefore, the questions asked by the Jagust and Kaufer labs are: does disruption of the blood-brain barrier lead to the deposition of beta-amyloid? Or does the deposition of beta-amyloid lead to disruption of the blood-brain barrier? Or are these two totally unrelated processes?
“To make a very long story short, we’re still in early stages, but we think there’s a correlation between the amount of beta-amyloid in the brain and the amount the blood-brain barrier is disrupted,” Jagust explains. “But this still doesn’t tell us the mechanism. It’s just a correlation.” That’s why collaboration between the Jagust and Kaufer labs is critical. The Kaufer lab is able to probe this mechanism by strengthening and weakening the blood-brain barrier in mouse models of Alzheimer’s disease that have beta-amyloid pathology. Overall, this collaboration represents a unique bridge connecting the cognitive and molecular ends of neurodegenerative research. “[This project] is a way to take observations in humans and dig into the mechanisms that underlie them, because if those things really are linked, then that’s a whole new pathway for therapy,” Jagust affirms.
From molecules to memory and from memory to molecules
Neuroscientists at UC Berkeley are taking robust, multifaceted approaches to understand the brain’s vast complexity. Together, they contribute to a growing body of work that comprehensively probes the nature of neurodegeneration, from its origins to its potential treatments. Approaching this complex, multi-layered set of diseases requires new and unique tactics that increasingly cross the lines of sub-disciplines. Ultimately, the future of neurodegenerative research lies at the intersection of different specialties. The cross-departmental nature of UC Berkeley’s HWNI has made it a leader in that effort.
Walking out of last October’s HWNI retreat, having just heard from a myriad of scientists studying the brain on all levels, one was left awestruck with just how complex understanding the brain is. And yet, despite the daunting nature of that challenge, there was a persistent sense of hope that all those researchers, with their disparate interests and techniques, might just pull it off, together.
Gergey Alzaem Mousa is a graduate student in neuroscience
Design by Kristina Boyko
This article is part of the Spring 2022 issue.
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