Frontotemporal dementia therapy by increasing the level of the FUS protein

Description: Abnormal clumps of the protein FUS (fused in sarcoma) and significantly lower levels of the protein progranulin (PGRN) have been found in frontotemporal dementia patients. Both FUS and PGRN could be associated with inflammation. However, prolonged inflammation can trigger diseases such as frontotemporal dementia. It was hypothesized that FUS and progranulin counteract inflammation by inhibiting the NF-κB inflammatory pathway, a major cellular signaling pathway that plays a key role in regulating inflammation. It was proposed that loss of functional FUS and progranulin results in chronic inflammation because this pathway becomes overactive. Subsequently, frontotemporal dementia develops. It was tested whether drugs increasing functional FUS and progranulin levels could prove to be promising treatments for frontotemporal dementia.

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Short Background

Frontotemporal dementia

Frontotemporal dementia (FTD) is a condition resulting from the progressive deterioration of the frontal lobe of the brain. Over time, the degeneration may advance to the temporal lobe. Second only to Alzheimer's disease (AD) in prevalence, FTD accounts for 20% of pre-senile dementia cases. Symptoms can begin to appear on average around 45 to 65 years of age, regardless of gender. The most common symptoms include significant changes in social and personal behavior, as well as a general blunting of emotions. Currently, there is no cure to FTD, but there are treatment options available that help alleviate the symptoms.

Frontotemporal lobar degeneration (FTLD) is the name for a group of clinically, pathologically and genetically heterogeneous disorders associated with atrophy in the frontal lobe and temporal lobe of the brain, with sparing of the parietal and occipital lobes. In some patients the symptoms of FTLD and Alzheimer's may overlap.

FTLD is the pathological term for the clinical syndrome of frontotemporal dementia (FTD). FTD differs from the more common Alzheimer's dementia in that memory is relatively well preserved, instead the disease presents with a more temporal-lobe phenotype.

RNA-binding protein FUS (Fused in Sarcoma) is a protein that in humans is encoded by the FUS gene.

There have been numerous advances in descriptions of genetic causes of FTLD, and the related disease Amyotrophic lateral sclerosis.

Mutations in the Progranulin gene (PGRN) can cause a FTLD presenting with TDP-43 pathology (FTLD-TDP43). Patients with Progranulin mutations have type 3 ubiquitin-positive, TDP-43 positive, tau-negative pathology at post-mortem. Progranulin is associated with tumorgenesis when overproduced, however the mutations seen in FTLD-TDP43 produce a haploinsufficiency, meaning that because one of the two alleles is damaged, only half as much Progranulin is produced.

Source: Wikipedia (All text is available under the terms of the GNU Free Documentation License and Creative Commons Attribution-ShareAlike License.)

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