Summary: Researchers have identified a common mechanism in both frontotemporal dementia and neuronal ceroid lipofuscinosis.

Source: Gladstone Institute.

Lipofuscis deposits accumulate in the retina of patients carrying mutations in the progranulin protein linked to neurological diseases.

Scientists at the Gladstone Institutes and the University of California, San Francisco (UCSF), identified a common mechanism in two forms of neurodegeneration that affect young adults or the elderly. The discovery advances efforts to find better treatments and cures for these diseases. Currently, there are no cures for these conditions, which are projected to cost the nation an estimated $259 billion in 2017.

The two forms of neurodegeneration are frontotemporal dementia (FTD) and neuronal ceroid lipofuscinosis (NCL). FTD is one of the most common forms of dementia in adults under 65 years. NCL is the most common neurodegenerative disease in children and young adults. This condition is associated with lipofuscin, the excessive accumulation of fats and proteins called lipopigments in vulnerable cells and tissues of the body.

The common factor in these diseases is the protein progranulin. Progranulin is involved in many biological processes, including inflammation, tumor formation, and normal development. It is widely expressed in the body, but changes in its expression mostly affect the brain. When progranulin levels are low, brain cells die more readily when exposed to toxins. Mutations that lower progranulin levels cause FTD, whereas complete loss of progranulin leads to NCL.

“Although FTD and NCL patients differ markedly in age and clinical manifestations, we wanted to know if humans who carry FTD-related genetic mutations in progranulin share features with NCL patients,” said Li Gan, PhD, associate director of the Gladstone Institute of Neurological Disease.

Identifying Lipofuscin in Humans at Risk for FTD

In a new study published in Science Translational Medicine, Gan’s team took a close look at lipofuscin in humans who carry mutations in the progranulin gene. Because vision loss is one of the first symptoms of NCL, and it is accompanied by lipofuscin accumulation in the retina, the researchers first evaluated lipofuscion in the retina using confocal scanning laser ophthalmoscopy. This non-invasive imaging technique is routinely performed in patients in the clinic.

“We found that people who carry progranulin mutations were nearly twice as likely to have retinal lipofuscin deposits than healthy people,” shared Michael Ward, MD, PhD, a former staff scientist at Gladstone who worked closely with Gan and was the lead author of the study. “Remarkably, they had a substantially increased number and size of lipofuscin deposits, even though they didn’t have any symptoms.”

Image shows the lipofuscis deposit on a retina.

After this initial discovery, the scientists evaluated the frontal cortex, the region of the brain most affected in FTD. Using postmortem tissues, Gan’s team found that lipofuscin deposits also accumulated in neurons from the frontal cortex of people carrying progranulin mutations.

Lipofuscin as a Diagnostic and Therapeutic Tool

To diagnose NCL, patients often undergo testing to determine the amount of lipofuscin in peripheral blood lymphocytes, a type of white blood cell. The researchers found higher levels of NCL-like lipofuscin in lympohblasts, cells that mature into lymphocytes,in patients with NCL, and also in asymptomatic patients carrying mutations in the progranulin gene. They then restored progranulin levels to normal in these cells, which reduced the levels of NCL-like lipofuscin.

“Our study shows that lipofuscin in the retina and in blood cells could serve as an early marker of disease,” said Gan, who is also a professor of neurology at UCSF. “Importantly, it also suggests that restoring the levels of progranulin to normal will prevent or help treat multiple neurodegenerative disorders.”

Future studies will clarify if lipofuscin itself causes disease and whether progranulin directly contributes to lipofuscin accumulation and neuronal loss.

ABOUT THIS NEUROSCIENCE RESEARCH ARTICLE

Other Gladstone researchers on the study include Robert Chen, Connor Ludwig, Maria Telpoukhovskaia, Ali Taubes, Sakura S. Minami, Meredith Reichert, and Shannon Leslie. Researchers from the UCSF, National Institutes of Health, National Taiwan University Hospital (Taiwan), Université de Nantes (France), Heinrich-Heine University Duesseldorf (Germany), Northwestern University Feinberg School of Medicine, Stanford Medical School, University of British Columbia, Vancouver (Canada), Harvard Medical School, and Veterans Affairs Medical Center, San Francisco also took part in the research.

Funding: Funding was provided by the National Institutes of Health; Bluefield Foundation, American Brain Foundation; That Man May See, Research to Prevent Blindness; National Eye Institute; Consortium for Frontotemporal Dementia Research; VA Merit Awards; Alzheimer’s Disease Center; Philippe Foundation; National Multiple Sclerosis Society.

Source: Megan McDevitt – Gladstone Institute
Image Source: NeuroscienceNews.com image is credited Gladstone Institutes, Giovanni Maki.
Original Research: Abstract for “Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis” by Michael E. Ward, Robert Chen, Hsin-Yi Huang, Connor Ludwig, Maria Telpoukhovskaia, Ali Taubes, Helene Boudin, Sakura S. Minami, Meredith Reichert, Philipp Albrecht, Jeffrey M. Gelfand, Andres Cruz-Herranz, Christian Cordano, Marcel V. Alavi, Shannon Leslie, William W. Seeley, Bruce L. Miller, Eileen Bigio, Marek-Marsel Mesulam, Matthew S. Bogyo, Ian R. Mackenzie, John F. Staropoli, Susan L. Cotman, Eric J. Huang, Li Gan and Ari J. Green in Science Translational Medicine. Published online April 12 2017 doi:10.1126/scitranslmed.aah5642

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Abstract

Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis

Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous GRN mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous GRN mutation carriers. Lymphoblasts from heterozygous GRN mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous GRN mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-associated FTD and GRN-associated NCL.

“Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis” by Michael E. Ward, Robert Chen, Hsin-Yi Huang, Connor Ludwig, Maria Telpoukhovskaia, Ali Taubes, Helene Boudin, Sakura S. Minami, Meredith Reichert, Philipp Albrecht, Jeffrey M. Gelfand, Andres Cruz-Herranz, Christian Cordano, Marcel V. Alavi, Shannon Leslie, William W. Seeley, Bruce L. Miller, Eileen Bigio, Marek-Marsel Mesulam, Matthew S. Bogyo, Ian R. Mackenzie, John F. Staropoli, Susan L. Cotman, Eric J. Huang, Li Gan and Ari J. Green in Science Translational Medicine. Published online April 12 2017 doi:10.1126/scitranslmed.aah5642