[The] UC San Diego-led team will receive a $9 million grant from the Aligning Science Across Parkinson’s (ASAP) initiative to help advance this research and position it for the next phases of drug development. ASAP is a coordinated research initiative to advance targeted basic research for Parkinson’s disease. Its mission is to accelerate the pace of discovery and inform the path to a cure through collaboration, research-enabling resources and data-sharing. The Michael J. Fox Foundation for Parkinson’s Research is the implementation partner for ASAP and issuer of the grant, which contributes to the Campaign for UC San Diego.

“This grant is supporting some of the most incredible progress being made in the Parkinson’s sphere. It’s a game-changing strategy that we hope will improve how Parkinson’s is treated,” said David Brenner, MD, vice chancellor of Health Sciences. “We are grateful to ASAP for making these advancements possible.”

In Neurodegenerative Diseases, Brain Immune Cells Have a “Ravenous Appetite” for Sugar

At the beginning of neurodegenerative disease, the immune cells of the brain – the “microglia” – take up glucose, a sugar molecule, to a much greater extent than hitherto assumed. Studies by the DZNE, the LMU München and the LMU Klinikum München, published in the journal “Science Translational Medicine”, come to this conclusion. These results are of great significance for the interpretation of brain scans depicting the distribution of glucose in the brain. Furthermore, such image-based data could potentially serve as a biomarker to non-invasively capture the response of microglia to therapeutic interventions in people with dementia.

In humans, the brain is one of the organs with the highest energy consumption, which can change with age and also due to disease – e. g. as a result of Alzheimer’s disease. “Energy metabolism can be recorded indirectly via the distribution of glucose in the brain. Glucose is an energy carrier. It is therefore assumed that where glucose accumulates in the brain, energy demand and consequently brain activity is particularly high,” says Dr. Matthias Brendel, deputy director of the Department of Nuclear Medicine at LMU Klinikum München.

The measuring technique commonly used for this purpose is a special variant of positron emission tomography (PET), known as “FDG-PET” in technical jargon. Examined individuals are administered an aqueous solution containing radioactive glucose that distributes in the brain. Radiation emitted by the sugar molecules is then measured by a scanner and visualized. “However, the spatial resolution is insufficient to determine in which cells the glucose accumulates. Ultimately, you get a mixed signal that stems not only from neurons, but also from microglia and other cell types found in the brain,” says Brendel.

Cellular Precision

“The textbook view is that the signal from FDG-PET comes mainly from neurons, because they are considered the largest consumers of energy in the brain,” says Christian Haass, research group leader at DZNE and professor of biochemistry at LMU Munich. “We wanted to put this concept to the test and found that the signal actually comes predominantly from the microglia. This applies at least in the early stages of neurodegenerative disease, when nerve damage is not yet so advanced. In this case, we see that the microglia take up large amounts of sugar. This appears to be necessary to allow them for an acute, highly energy-consuming immune response. This can be directed, for example, against disease-related protein aggregates. Only in the later course of the disease does the PET signal appear to be dominated by neurons.”

The findings of the Munich researchers are based on laboratory investigations as well as PET studies in about 30 patients with dementia – either Alzheimer’s disease or so-called four-repeat tauopathy. The findings are supported, for instance, by studies on mice whose microglia were either largely removed from the brain or, so to speak, deactivated. In addition, a newly developed technique was used that allowed cells derived from the brains of mice to be sorted according to cell type and their sugar uptake to be measured separately.

Consequences for Research and Practice

“FDG-PET is used in dementia research as well as in the context of clinical care,” Brendel says. “Insofar, our results are relevant for the correct interpretation of such brain images. They also shed new light on some hitherto puzzling observations. However, this does not call into question existing diagnoses. Rather, it is about a better understanding of the disease mechanisms.”

Haass draws further conclusions from the current results: “In recent years, it has become evident that microglia play a crucial, protective role in Alzheimer’s and other neurodegenerative diseases. It would be very helpful to be able to monitor the activity of these cells non-invasively, for example their response to drugs. In particular, to determine whether a therapy is working. Our findings suggest that this may be possible by PET.”

(Image caption: DAXX (red color at top) prevents the aggregation of mutant p53 protein associated with cancers (dark green color at bottom) in cells).

Restoring “Chaperone” Protein May Prevent Plaque Build-up in Alzheimer’s

For the first time, Penn Medicine researchers showed how restoring levels of the protein DAXX and a large group of similar proteins prevents the misfolding of the rogue proteins known to drive Alzheimer’s and other neurodegenerative diseases, as well as certain mutations that contribute to cancers. The findings could lead to new targeted approaches that would restore a biological system designed to keep key proteins in check and prevent diseases.

The findings were published online in Nature.

The study focuses on DAXX, or death domain-associated protein, which is a member of a large family of human proteins, each with an unusually high content of two specific amino acid residues, aspartate and glutamate, referred to as polyD/E proteins. The various roles of DAXX and approximately 50 other polyD/E proteins in cell processes have emerged over time, but their role as a protein quality control system — a “chaperone” that directs protein folding, so to speak — was unanticipated.

“We solve a decades-long puzzle by showing this group of proteins actually constitute a major protein quality control system in cells and a never-before-seen enabler of proper folding of various proteins — including misfolding-prone proteins associated with various diseases,” said senior author Xiaolu Yang, PhD, a professor of Cancer Biology in the Perelman School of Medicine at the University of Pennsylvania. “Keep that family of proteins functioning properly, and the tangling of rogue proteins may be diminished or stopped altogether.”

Proteins are the workhorses of the cell. To ensure normal cellular function and protect against protein-misfolding associated with disease, organisms have evolved elaborate protein quality control systems to enable efficient protein folding. However, these systems, especially those in humans, are still not well understood, which limits the ability to develop effective therapies.

The researchers showed that DAXX and other polyD/E proteins facilitate the folding of proteins, reverse protein aggregates, and unfold misfolded proteins. They prevent neurodegeneration-associated proteins, such as beta-amyloid and alpha-synuclein from misfolding, tangling, and forming extracellular plaques and intracellular inclusions, they found. Beta-amyloid clumping between the nerve cells is observed in the brains of Alzheimer’s disease patients and the target of many treatment approaches, while intracellular inclusions of alpha-synuclein are observed in the brains of patients with Parkinson’s disease.

The team also showed DAXX’s potential role in treating cancer.

DAXX restores native function to tumor-associated and aggregation-prone p53 proteins, reducing their cancer properties. That’s important because p53 is the preeminent tumor suppressor and mutations in p53 are associated with a bevy of cancers, including lung, colon, pancreatic, ovarian, and breast cancer. Bolstering DAXX function, the authors said, might represent an alternative approach to therapeutically reestablish the tumor suppressive function of mutant p53 to treat patients.

“The findings give us a better understanding of a new biochemical activity that effectively contends with protein misfolding seen in Alzheimer’s and other neurodegenerative diseases, as well as in cancer, and represent an opportunity to develop new approaches to treat these diseases,” Yang said.