“Genetics is now widely applied to diagnosis, monitoring and the search for a potential treatment of neurodegenerative diseases. The ability to detect carriers of causal mutations could help evaluate the efficacy of therapies in clinical trials of individuals at either the pre-symptomatic or early disease stages. The detection of genetic modifiers of neurodegenerative diseases, including frontotemporal lobar degeneration might increase the accuracy of predicting risk and/or age at onset in asymptomatic mutation carriers, which is important for genetic counselling in families and clinical trials focused on early intervention.”
-Dr. Ekaterina Rogeava
As the leading cause of dementia in patients who are diagnosed before 65, frontotemporal lobar degeneration (FTLD) is characterized by progressive declines in behavior and language that arise from degeneration in the frontal and anterior lobes of the brain. Encompassing many disorders, FTLD shares significant clinical and pathological overlap with progressive supranuclear palsy, corticobasal degeneration, and amyotrophic lateral sclerosis. Simply put, FTLD has a strong genetic basis with several genes that can be mutated.
At present, there is no cure.
To better understand the genetic basis of FTLD and its associated risk factors, a group of researchers – partly funded by the Canadian Consortium on Neurodegeneration in Aging – came together to carry out a genome-wide association study (GWAS). Broadly speaking, GWAS have made substantial contributions to our understanding of complex neurodegenerative diseases. For instance, the largest GWAS of Alzheimer’s disease identified key pathways of disease pathogenesis, including inflammation and immune response, lipid metabolism, and endocytosis.
This particular study, “Potential genetic modifiers of disease risk and age at onset in patients with frontotemporal lobar degeneration and GRN mutations: a genome-wide association study,” (recently published in Lancet Neurology and led by Rosa Rademakers) provides “new avenues towards biomarker discovery and the development of therapeutic approaches for patients with FTLD.”
To date, the availability of biomarkers, which are measurable disease associated factors (e.g. specific protein levels) have been limited when it comes to FTLD. Historically, tau was the only protein recognized as contributing to this neurodegenerative disease; as a result, biomarkers have been developed to focus almost exclusively on tau. More recently, it became clear that loss-of-function mutations in GRN and its associated protein are an important cause of FTLD. Therefore, the current study focused on carriers of GRN mutations, accounting for up to 20% of familial FTLD cases.
In more detail, the GRN gene provides instructions for how to make the protein granulin, which is found in tissues throughout the human body. This protein is most active in cells that divide rapidly, such as skin cells and the cells that line the gastrointestinal tract. It is granulin that is responsible for regulating the growth, division, and survival of these cells, not to mention regulating the body’s immune response and healing the body’s wounds.
The researchers’ data, obtained from 40 world-wide clinical centres, show that people with FTLD (who are also carrying a mutation of the GRN gene) are at either a greater or a lower risk of developing disease symptoms. What modifies their risk is whether they are carrying specific variations in the TMEM106B gene.
“We were able to estimate that GRN carriers of the TMEM106B protective haplotype have 50% lower odds of developing disease symptoms than carriers of the non-protective haplotype. We also newly identified the GFRA2 locus on chromosome 8p21.3 as a potential genome-wide significant modifier of disease risk in patients with GRN mutations. The lead variant at the GFRA2 locus (rs36196656) is located within GFRA2 intron 3 and affected the expression profile of GFRA2. Functional studies also showed that progranulin binds to GFRA2 in vitro.”
This knowledge will have implications for both diagnosis and treatment, which depend on successfully targeting specific pathological mechanisms of FTLD. The genetic variants may also “further inform genetic counseling in families and could aid in future clinical trial designs.”
According to Dr. Ekaterina Rogeava “better understanding of the functional mechanisms of the GRN-GFRA2-TMEM106B pathway might prove critical for identifying biomarkers and/or designing drugs to modify risk in GRN-driven disease. It would be important to evaluate if the reported molecular genetic findings also contribute to other neurodegenerative disorders. We are only at the beginning of a broad precision medicine approach targeting the clinical and biological complexity of these disorders and building the evidence base needed to more effectively guide clinical practice.”
Ekaterina Rogaeva, PhD
Professor (Department of Medicine, University of Toronto, Tanz CRND)
Chair in Research on Dementia with Lewy Bodies at Tanz CRND
Krembil Discovery Tower, Tanz Centre for Research in Neurodegenerative Disease (Tanz CRND)
The views and opinions expressed in this guest blog are those of the authors (individual CCNA scientists) and do not necessarily reflect the views of the Canadian Consortium on Neurodegeneration in Aging and its partner organizations.