For decades, scientists have focused heavily on developing therapies targeting amyloid proteins that accumulate in degenerative brains, but disappointing results have spurred efforts to find alternative approaches.
The latest research highlights the therapeutic potential of a lysosomal protein called progranulin, which the study found appears to play a pivotal role in how the cell breaks down lipids.
“A lack of progranulin in the cell’s lysosome causes dysfunction in the organelle, a situation that is characteristic of many neurodegenerative diseases. By finding ways to boost progranulin production, scientists may be able to prevent or treat different types of dementia such as frontotemporal lobar degeneration (FTLD),” said Dr. Joachim Herz, who led the study and is Director of UT Southwestern’s Center for Translational Neurodegeneration Research.
In the study published in Cell Reports, the Herz Lab examined brain tissue of humans and mice to demonstrate how lipids in the lysosome are regulated by progranulin. This and other proteins are deficient in the lysosome in nearly half of all inherited FTLD cases because of mutations in the progranulin gene.
However, these FTLD patients typically have only one mutated copy of the gene. The remaining normal copy of the gene can potentially be targeted by novel therapies to boost progranulin expression and production, said Dr. Bret Evers, the study’s co-first author.
“Determining the role of progranulin within the cell is of vital importance if new therapies are to be created,” said Dr. Evers, Assistant Instructor in the Department of Pathology.
In addition, the study documented how brain tissue that lacked progranulin showed a unique lipid pattern that was different from other neurodegenerative diseases such as Alzheimer’s disease, which had its own distinct lipid pattern.
These “lipid fingerprints” allow scientists to distinguish between conditions that otherwise have several overlapping symptoms, Dr. Evers said. In the future, lipid patterns may help clinicians diagnose disease in its early stages.
“Determining the type of neurodegenerative disorder early in its course before overt symptoms appear will provide patients with more treatment options that better target the underlying disorder to slow its progression,” Dr. Evers said.
About the study
The study was conducted in the Center for Translational Neurodegeneration Research, led by Dr. Herz, Professor of Molecular Genetics, Neuroscience, Neurology and Neurotherapeutics. He is supported by the Thomas O. and Cinda Hicks Family Distinguished Chair in Alzheimer’s Disease Research and the Presbyterian Village North Foundation Distinguished Chair in Alzheimer’s Disease Therapeutic Research.
Other study collaborators included Dr. Charles L. White, III, in the Department of Pathology; Rachel J. Tesla and Drs. Carlos Rodriguez-Navas, Catherine R. Wasser, and Kyoung Shin Yoo; Dr. Janine Prange-Kiel in the Department of Cell Biology; Dr. Florian Plattner in the Department of Psychiatry; Dr. Basar Cenik in the Departments of Psychiatry and Neuroscience; Dr. Jeffrey McDonald in the Center for Human Nutrition and the Department of Molecular Genetics; Dr. Gang Yu in the Department of Neuroscience; and Thomas A. Ravenscroft and Dr. Rosa Rademakers in the Department of Neuroscience at Mayo Clinic, Jacksonville, Fla.
The research was funded by the National Institutes of Health (Herz and Yu), the National Institute on Aging (Herz and White), the Consortium for Frontotemporal Dementia Research (Herz and Yu), the BrightFocus Foundation (Herz), the Alzheimer’s Association (Yu), the Clayton Foundation for Research (Herz), UT Southwestern Alzheimer’s Disease Center (White and Evers), and the Carl B. and Florence E. King Foundation Endowed Fund in Alzheimer’s Disease Research (Evers and White).