Novel Insights Into Neurodegenerative Diseases Linked to TDP-43

Researchers at the University of California at San Francisco (UCSF) recently revealed new insights into the pathogenesis of neurodegenerative diseases. The study, published in The Journal of Neuroscience, is entitled “The Progranulin Cleavage Products, Granulins, Exacerbate TDP-43 Toxicity and Increase TDP-43 Levels”.

Mutations in the gene progranulin are a major genetic cause of frontotemporal dementia (FTD), a group of disorders that mainly affects the frontal and temporal lobes of the brain, which are associated with personality, behavior and language. Depending on the brain area affected, symptoms may vary. Some patients experience dramatic changes in their personality, while others lose the ability to use language. It is estimated that FTD accounts for up to 10 – 15% of all diagnosed dementia cases.

Progranulin is a secreted growth factor that plays a role in biological processes like inflammation, wound healing, apoptosis (cell death) and stress responses, and has been linked to cancer and neurodegenerative diseases. Progranulin is processed into peptides known as granulins, although their exact role in the pathogenesis of neurodegenerative diseases is unknown. Interestingly, patients with only one functional copy of the progranulin gene develop FTD, while patients with no functional copies of the gene develop a different condition called neuronal ceroid lipufuscinosis (NCL), which is characterized by a progressive, permanent loss of motor and psychological ability.

TDP-43 is a protein previously reported to be deregulated in neurodegenerative diseases like FTD but also amyotrophic lateral sclerosis (ALS), a condition characterized by the gradual degeneration and atrophy of motor neurons in the brain and spinal cord that are responsible for controlling essential voluntary muscles, such as the ones related to movement, speaking, eating, and even breathing. TDP-43 protein, which is toxic to cells in high concentrations, is the main constituent of the pathological lesions observed in neurons of FTD and ALS patients.

The molecular interaction between progranulin and TDP-43 is not clear. In this study, researchers used the worm Caenorhabditis elegans as a model to determine how granulins contribute to the neurodegenerative process.

Researchers found that the complete loss of the progranulin gene did not worsen TDP-43 toxicity in neurons. In contrast, partial loss of the TDP-43 gene (one functional copy only as it happens in humans with FTD) led to increased toxicity, with worms moving one-third as often as normal worms. The results led the authors to suggest that the presence of granulins is important in a FTD context.

By analyzing granulins in more detail, researchers found that they have little effect on behavior by themselves, but when co-expressed with TDP-43, enhance its toxicity affecting several behaviors including motor coordination. “Granulins are synergistically toxic with TDP-43,” noted the study’s senior author Dr. Aimee Kao in a news release. The team found that granulins induce an increase in TDP-43 protein levels. When analyzing tissues from deceased FTD patients with TDP-43 protein deposits, researchers found that granulins accumulate specifically at the diseased brain regions.

The research team concluded that granulins increase TDP-43 protein levels, intensifying its toxicity effects, and emphasized that this is the first report of a toxic role for granulins in a neurodegenerative disease model. Researchers believe that the presence of granulins may contribute to diseases linked to TDP-43 disorders like FTD and ALS.

“The involvement of the granulins is definitely worth looking into in other models and in people.” concluded Dr. Jiou Wang from Johns Hopkins University in Baltimore, who was not involved in the study. The team believes that their findings are important for FTD therapeutic approaches focused on boosting progranulin levels as more progranulin may actually lead to more granulins resulting in worst disease outcomes.