In a recent study in Molecular Neurodegeneration, researchers from VIB-KU Leuven led by prof. Philip Van Damme, reveal neuroprotective effects of progranulin against TDP-43 accumulation and neurodegeneration. The findings suggest that progranulin treatment may not only be of interest to certain patients with frontotemporal dementia, but also to patients with ALS.
Frontotemporal dementia and ALS: two distinct diseases with a shared pathology
Frontotemporal dementia or FTD is the second most common form of early onset dementia, after Alzheimer’s disease. Patients generally present with changes in behavior, such as apathy or disinhibition, or with language problems. Eventually, these symptoms make normal social interaction impossible. Unfortunately, there is currently no treatment, and FTD patients usually pass away 6 to 8 years after the first symptoms appear.
In about half of the patients, TDP-43 protein aggregates are found in the brain. In a common familial form of the disease, caused by shortage of the growth factor progranulin, accumulation of TDP-43 occurs as well, but scientists don’t fully understand why.
Another neurodegenerative disease with TDP-43 accumulation in the brain is amyotrophic lateral sclerosis or ALS. ALS patients suffer from muscle weakness and wasting, because their motor neurons degenerate. The muscles responsible for swallowing and breathing can also be affected, making ALS extremely deadly. Most patients pass away two to five years after symptom onset.
Although the disease presentation of ALS differs greatly from FTD, almost all patients with ALS have similar TDP-43 protein accumulation. Missense mutations in the gene encoding TDP-43 are a rare cause of ALS, another clue that abnormal TDP-43 protein function plays a role in ALS.
Progranulin and TDP-43
In a new study led by Prof. Philip Van Damme (VIB-KU Leuven and University Hospitals Leuven), researchers from the lab of Neurobiology at the Center for Brain & Disease Research studied the connection between progranulin and TDP-43 in a murine model.
Mice with a specific mutation in the TDP-43 gene have widespread accumulation of insoluble TDP-43 and develop disease symptoms, but progranulin could reduce the levels of insoluble TDP-43. This attenuated the loss of large axon fibers in the spinal cord, and slowed down disease progression was significantly.
Philip Van Damme: “Our findings suggest that progranulin can indeed prevent accumulation of insoluble TDP-43 and slow down TDP-43-induced neurodegeneration. This suggests that treatment avenues focused on progranulin may not only be of interest to certain patients with frontotemporal dementia, but also to ALS patients.”
Progranulin reduces insoluble TDP-43 levels,slows down axonal degeneration andprolongs survival in mutant TDP-43 mice, Beel et al., Molecular Neurodegeneration 2018
Questions from patients
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