Tauopathies and Genetic Influences in Neurodegenerative Diseases

Tauopathies constitute a group of neurodegenerative disorders characterised by the abnormal aggregation of tau protein within neurons and glial cells. The microtubule-associated protein tau (encoded by MAPT) normally stabilises axonal microtubules, but in disease states tau becomes hyperphosphorylated, detaches from microtubules and forms insoluble inclusions, leading to synaptic dysfunction and neuronal loss. Clinically, tauopathies manifest with a spectrum of cognitive, motor and behavioural symptoms, encompassing conditions such as Alzheimer’s disease, progressive supranuclear palsy, corticobasal degeneration and frontotemporal dementia. Genetic studies have established that common haplotypes and rare variants in MAPT, as well as loci in genes involved in protein homeostasis, inflammation and cytoskeletal regulation, influence disease susceptibility and progression. Emerging evidence highlights structural variants and epigenetic modifications as additional layers of genetic risk. Deciphering these genetic contributions is central to unravelling pathogenic mechanisms, identifying biomarkers for early diagnosis and pursuing tau-directed therapeutic strategies with global relevance.

Research from Nature Portfolio

Genome-wide association analysis in corticobasal degeneration has delineated novel susceptibility loci beyond the MAPT H1 haplotype, including regions at MOBP and a long non-coding RNA adjacent to KIF13B, and confirmed shared genetic risk with progressive supranuclear palsy. These findings underscore a convergent genetic architecture among tauopathies and nominate myelin-associated and cytoskeletal pathways as targets for intervention. Fine-mapping of the 17q21.31 region has further resolved independent risk signals at MAPT and neighbouring genes, refining the landscape of haplotype-mediated disease risk and informing the design of functionally based therapeutic programmes.

Tauopathies and Genetic Influences in Neurodegenerative Diseases publication trend

The graph below shows the total number of articles in tauopathies and genetic influences in neurodegenerative diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Tauopathy: A neurodegenerative condition characterised by pathological aggregation of tau protein in neural tissue.

Hyperphosphorylation: Excessive addition of phosphate groups to a protein, often altering its function or solubility.

Haplotype: A set of genetic variants on a chromosome inherited together that can influence disease risk.

Structural variant: A genomic alteration involving segments of DNA that are deleted, duplicated, inverted or translocated.

Genome-wide association study (GWAS): An analysis scanning the genome for common variants that occur more frequently in individuals with a particular disease than in controls.

References

1. Whole-genome sequencing analysis reveals new susceptibility loci and structural variants associated with progressive supranuclear palsy. Molecular Neurodegeneration (2024).
2. Loss of Smek1 Induces Tauopathy and Triggers Neurodegeneration by Regulating Microtubule Stability. Advanced Science (2024).
3. Genome-wide association study of corticobasal degeneration identifies risk variants shared with progressive supranuclear palsy. Nature Communications (2015).