Unraveling the Key to Suppressing Protein Misfolding in Neurodegenerative Diseases

Proteins known as oligomeric chaperones help suppress the formation of misshaped proteins that cause a variety of degenerative and neurodegenerative diseases, such as Alzheimer's, Huntington's, and Parkinson's. In a new study, UT Southwestern Medical Center researchers identified a key feature necessary for one of these oligomeric chaperones, known as DNAJB8, to assemble from disparate parts and showed that the parts alone can reshape misfolded proteins. The findings, published in Structure, could lead to better ways to diagnose and treat these conditions.

Now that we know more about how these oligomeric chaperones work, we could potentially tailor them to be more specific for disease proteins so they'll work even better."

Lukasz Joachimiak, Ph.D., Study Leader, Associate Professor in the Center for Alzheimer's and Neurodegenerative Diseases and of Biochemistry at UT Southwestern

Dr. Joachimiak, an Effie Marie Cain Scholar in Medical Research, is an Investigator in UTSW's Peter O'Donnell Jr. Brain Institute.

All proteins are produced in the body in a linear chain, made of amino acid building blocks sequentially strung together. But to perform their diverse roles in the body, these chains need to fold into precise shapes. While some chaperones sculpt proteins into these folded conformations at the ribosomes, which are the cells' protein production factories, others like DNAJB8 scour cells for misfolded proteins and either correct their conformation or send them elsewhere in cells for further processing. By steering misfolded proteins back into the correct conformation, DNAJB8 and some other oligomeric chaperones prevent misfolded proteins from intertwining and forming clumps that cause many degenerative and neurodegenerative diseases. They become key gatekeepers to prevent the diseases from starting.

Scientists have long known that DNAJB8 can exist both as individual units, called monomers, or as an assembly of monomers known as an oligomer. Previous studies showed that mutating these proteins in various ways prevented assembly into oligomers and stopped their ability to correct misfolded proteins. However, the exact part of DNAJB8 that's necessary for assembly into oligomers was unknown, and the role of its monomers was unclear.

"We needed to decouple the ability of this chaperone to assemble from its ability to prevent misfolding of proteins," Dr. Joachimiak explained.

To do this, the researchers mutated individual amino acids that make up DNAJB8. They found that swapping a single amino acid known as phenylalanine 151 to a different amino acid prevented DNAJB8 from forming oligomers both in a test tube and in cells.

Using this altered form of DNAJB8 that stayed in monomeric form, Dr. Joachimiak and his colleagues showed that these monomers readily bound to and reshaped misfolded tau protein – a causative agent in Alzheimer's disease – but did not affect correctly folded tau. The same was true for misfolded Htt, the protein involved in Huntington's disease. These findings suggest that the monomers, rather than the oligomers, are the active component in correcting misfolded proteins.

One theory is that the oligomer serves as a storage depot for monomers, which do the real work of suppressing protein misfolding. It's an idea that the Joachimiak Lab will test in future studies. Dr. Joachimiak and his colleagues also plan to test whether further altering these monomers could make them useful for diagnosing diseases marked by protein misfolding or more effective in correcting misfolding in specific proteins for use as possible therapies.

Other UTSW researchers who contributed to this study include first author Bryan D. Ryder, Ph.D., former graduate student researcher in the Joachimiak Lab; Marc I. Diamond, M.D., Director of the Center for Alzheimer's and Neurodegenerative Diseases and Professor of Neurology and Neuroscience; Ayde Mendoza-Oliva, Ph.D., Instructor in the Center for Alzheimer's and Neurodegenerative Diseases and of Biochemistry; and Joachimiak Lab members Pawel M. Wydorski, M.S., graduate student researcher, Paulina Macierzynska, M.S., graduate student assistant, and Nabil Morgan, Research Technician.

This study was funded in part by National Institutes of Health (NIH) grants (RF1AG065407 and RF1AG078888) with work performed at the Electron Microscopy Core Facility at UTSW, which is also supported by NIH grants (1S10OD021685-01A1 and 1S10OD020103-01).

Dr. Diamond holds the Effie Marie Cain Distinguished University Chair in Alzheimer's Research.

Source:
Journal reference:

Ryder, B. D., et al. (2024). DNAJB8 oligomerization is mediated by an aromatic-rich motif that is dispensable for substrate activity. Structure. doi.org/10.1016/j.str.2024.02.015.

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