Science Overview

Frontotemporal dementia is a neurodegenerative disease, which means that affected neurons degenerate and ultimately die. The death of these cells causes the specific personality changes seen in frontotemporal dementia. Why and how these neurons die are questions that The Bluefield Project is helping to solve.

Do mutations in genes cause frontotemporal dementia?

Approximately 20 to 50 percent of frontotemporal dementia cases appear to be hereditary, meaning that a mutation in a specific gene is known to cause that individual’s frontotemporal dementia and it can be passed down from generation to generation.

Currently, mutations in six genes – tau (MAPT), progranulin (GRN), chromosome 9 open reading frame 72 (C9ORF72), TAR DNA binding protein (TARDBP), valosin-containing protein (VCP) and charged multivesicular body protein (CHMP2B) -- are linked to frontotemporal dementia. The most common genetic causes of frontotemporal dementia are mutations in the C9ORF72, MAPT and GRN genes.

Do specific mutations cause specific forms of frontotemporal dementia?

We are just starting to understand whether mutations in certain proteins preferentially cause one form of frontotemporal dementia versus another. GRN mutations are linked to bvFTD, PNFA, and movement disorders, although usually not ALS. Mutations in C9ORF72 cause both frontotemporal dementia and ALS. VCP mutations are associated with both frontotemporal dementia and another disease, Paget disease of bone. CHMP2B mutations are associated with frontotemporal dementia, FTD-ALS, and ALS. They are quite rare, so far having been found only in a single Danish family. TARDBP mutations cause both sporadic and familial ALS. It is possible additional genes will be identified in the future.

How mutations in these genes cause frontotemporal dementia is the focus of much research – these genes provide the molecular handle needed to discover and interrogate the cascade of what goes wrong in the brains of frontotemporal dementia patients. By understanding how mutations change the functions of these proteins and lead to disease, researchers will be able to design therapeutic strategies for curing frontotemporal dementia.

What is progranulin (GRN)?

Progranulin is a gene that, when mutated, causes frontotemporal dementia. Dozens of disease-causing progranulin mutations are known and they all result in lowered levels of progranulin protein. Thus, not having enough progranulin protein eventually causes neurons in the frontal and temporal lobes to die. If not having enough progranulin causes frontotemporal dementia, then restoring progranulin levels should prevent or possibly cure frontotemporal dementia. Because of this straightforward possibility, several CFR researchers are developing ways to increase progranulin levels as potential therapeutics.

Why not having enough progranulin causes frontotemporal dementia is unknown, but it’s the question driving research in frontotemporal dementia labs around the world. Progranulin is involved in a diverse range of biological processes including inflammation, tumorigenesis, development and wound repair. It is widely expressed in most tissues in the body, but it’s not necessary for life. Model animals, like mice and worms, can live and reproduce even without progranulin. Why loss of progranulin seems to preferentially impact the brain even though it’s involved in a host of processes is unknown.

What does loss of progranulin do to brain cells?

The end result is that loss of progranulin causes brain cells to die. We don’t understand how this happens, but this is one of the major research focuses within the CFR. Recent data suggest that loss of progranulin results in an abnormal immune response in the brain – researchers are working to understand how this might cause neuron death.

WHAT IS TAU?

Tau is the protein encoded by the MAPT gene. Tau normally interacts with a protein called tubulin to help promote and stabilize the formation of microtubules. In neurons, microtubles are an important component of axons and serve as paths for transport of signals and nutrients along their lengths.

In patients with mutations in the MAPT gene, the tau protein is altered and forms abnormal clumps. It is thought that these alterations impair neuronal function, ultimately leading to cell death and disease. Tau clumps are also sometimes found in the brains of Alzheimer’s Disease patients, although typically these patients do not have MAPT mutations. Exactly how tau mutations cause frontotemporal dementia is an active area of research.

WHAT IS TDP-43?

TDP-43 is a protein encoded by the TARDBP gene. It is normally found in the nucleus of cells where it regulates many cellular processes including RNA transcription, splicing, and transport. In many patients with frontotemporal dementia, including those with GRN mutations, abnormal accumulation of TDP-43 outside of the nucleus is observed. Patients with MAPT mutations do not exhibit TDP-43 abnormalities. Interestingly, TDP-43 accumulation is seen in another neurodegenerative disease, amyotophic lateral sclerosis (ALS), also known as Lou Gehrig’s Disease.

WHAT IS VCP?

Mutations in VCP or valosin-containing protein have also been shown to cause familial frontotemporal dementia. VCP is a member of a class of proteins known as the AAA+ ATPase family and is known to be involved in a number of cellular functions, including how proteins and cellular components are degraded. Mutations in VCP have recently been found to cause ALS, strengthening the notion that frontotemporal dementia and ALS are part of a disease spectrum.

WHAT IS CHMP2B?

Mutations in the CHMP2B gene are a rare cause of frontotemporal dementia. CHMP2B is involved in a cellular process known as endosomal trafficking. Patients with mutations in CHMP2B do not exhibit abnormal accumulation of tau or TDP-43.

WHAT IS A CELLULAR INCLUSION?

A cellular inclusion is an abnormal accumulation of proteins that builds up within a cell. Upon autopsy, brain tissue from frontotemporal dementia patients often shows cellular inclusions. The two most common types of cellular inclusions seen in frontotemporal dementia patients are those caused by accumulation of tau protein and those caused by accumulation of TDP-43. Originally thought to be the cause of cell death, some investigators now believe that formation of these inclusions is a normal, protective response of a cell to damage. Exactly how and if cellular inclusions cause cells to die is studied by a number of labs throughout the world.