"The new findings zero in on the MAPT gene. That gene makes a protein called tau, which also has been associated with cognitive decline in Alzheimer's disease. Identifying the downstream effects of the mutation could help identify new treatment targets for frontotemporal dementia, Alzheimer's disease and other tau-related illnesses, including Parkinson's disease."
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Credit: ColiN00B Scientists have identified the molecular mechanism that leads to the death of neurons in amyotrophic lateral sclerosis (also known as ALS or motor neurone disease) and a common form of frontotemporal dementia.
Frontotemporal dementia is a form of dementia that causes changes in personality and behaviour, and language difficulties.
In frontotemporal dementia and ALS, the proteins become permanently stuck as abnormally dense gels, trapping the RNA and making it unavailable for use.
In frontotemporal dementia, the abnormal gelling was found to be caused by defects in the chemical modification of FUS.
In motor neuron disease, it was caused by mutations in the FUS protein itself which meant it was no longer able to change form.
They found a robust overlap between ALS and frontotemporal dementias, including corticobasal degeneration and progressive supranuclear palsy, but not between ALS and Parkinson’s or ALS and Alzheimer’s disease.
The ALS data set comprised 31 independent cohorts, including 12,577 patients and 23,475 controls (Van Rheenen et al., 2016).
Shared Risk.
Indeed, a recent paper reported slower axonal transport in neurons derived from healthy MAPTH1 carriers (Beevers et al., 2017).
To dissect potential effects of the shared SNPs, the authors looked for expression quantitative trait loci that associated with them.
Genetic mutations in two previously unrecognized genes, the microtubule-associated protein tau (MAPT) and BNIP1 genes, are associated with elevated risk for amyotrophic lateral sclerosis (ALS).
As seen in other neurodegenerative diseases, abnormal accumulation of toxic proteins seems to play a role in ALS onset and progression.
Different mutations in tau protein previously were associated with other neurodegenerative diseases, such as Alzheimer’s.
However, the specific mutation identified in this study was associated only with ALS, and not with the other diseases included in the study.
Genetic mutations that modestly elevate risk for ALS were identified with more than two dozen different genes.