Lack of Granulin Proteins — Once Considered Villains — Might Contribute to Parkinson’s, Study Suggests

Brain proteins called granulins — previously thought to be toxic — might play a crucial role in brain health, according to a study that suggests the proteins might be linked to several neurodegenerative diseases, including Parkinson’s.

The identification of a new tool to track the proteins allowed Emory University School of Medicine researchers to conclude that granulins are part of cellular waste disposal and recycling centers called lysosomes.

“A lysosomal function for granulins is exciting and novel. We believe it may provide an explanation why decreased levels of granulins are linked to multiple neurodegenerative diseases, ranging from frontotemporal dementia to Alzheimer’s,” Thomas Kukar, PhD, an assistant professor of pharmacology and neurology at Emory and the study’s senior author, said in a press release.

The study, “Intracellular Proteolysis of Progranulin Generates Stable, Lysosomal Granulins That Are Haploinsufficient in Patients with Frontotemporal Dementia Caused by GRN Mutations,” used the newly developed tool to track these proteins in cells from patients with frontotemporal dementia.

Granulins are produced from a parent protein called progranulin. Mutations affecting one copy of this gene can cause frontotemporal dementia. If both copies are mutated, people develop the rare condition neuronal ceroid lipofuscinosis.

This neurodegenerative condition is a lysosomal storage disorder in which defective lysosomes cause cells to be littered with fat and protein aggregates. It provided one of the clues for the team that the proteins do, in fact, play an important role in the brain.

Parkinson’s disease has also been linked to progranulin. Earlier research showed that Parkinson’s patients have lower levels of progranulin, and a mouse study demonstrated that boosting progranulin production with gene therapy protected dopamine neurons from degeneration.

Researchers also believe that lysosome abnormalities contribute to Parkinson’s disease.

“Over the past few years, evidence has accumulated that progranulin deficiency impairs the function of lysosomes, but scientists still don’t know why,” said Chris Holler, PhD, lead study author.

Their findings, described in the journal eNeuro, showed that progranulin enters lysosomes within cells, were it is then broken down to the smaller granulins. In contrast to most proteins that enter the lysosome, these were not degraded, suggesting they play a role in lysosomal function.

“Although some people suspected that progranulin gets cleaved in the lysosome, it could not be proven,” Holler said. “Our paper is the first to actually show that mature granulins are made in the lysosome.”

The team now aims to use their new tools to explore what the granulins are doing in lysosomes, hoping to gain insights that might lead to new treatment options.