Genetic Mechanisms in Neurodegenerative Diseases

Neurodegenerative diseases such as Alzheimer’s, Parkinson’s and frontotemporal dementia arise from complex interactions between inherited variants, somatic mutations and the cellular machinery that maintains neuronal integrity. Mendelian forms of Alzheimer’s disease are driven by mutations in genes encoding amyloid precursor protein and presenilin enzymes, whereas risk alleles such as APOE4 and TMEM106B influence susceptibility to late‐onset disease. Beyond classical inheritance, post‐zygotic somatic mutations in neurons can perturb signalling pathways that govern tau phosphorylation and synaptic function. Aberrant lysosomal and autophagic processes, often linked to genetic polymorphisms in lysosomal exonucleases, compromise the clearance of protein aggregates and mitochondrial debris. Collectively, these genetic mechanisms converge on pathways of protein homeostasis, endolysosomal trafficking and neuroinflammation, offering routes to novel therapeutic interventions.

Research from Nature Portfolio

Recent studies have elucidated how defects in lysosomal nucleotide metabolism contribute to Alzheimer’s pathophysiology. One investigation revealed that variants in a lysosomal exonuclease lead to accumulation of mitochondrial DNA within neuronal lysosomes, triggering cGAS–STING signalling, enhanced mitophagy and aberrant processing of amyloid precursor fragments. Pharmacological inhibition of the cGAS–STING axis restored cholesterol and amyloid precursor processing to normal levels. In parallel, work on axonal spheroids demonstrated that overexpression of the same lysosomal protein in a mouse model of Alzheimer’s disease promotes the growth of endolysosomal vesicles within spheroids, creating conduction blockades that disrupt neural network function. Deletion of this gene reduced vesicle accumulation, improved electrical conduction and reversed network dysfunction independently of amyloid burden.

Genetic Mechanisms in Neurodegenerative Diseases publication trend

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

Technical terms

Polymorphism: A genetic variant that can exist in multiple forms within a population, influencing disease susceptibility.

Lysosome: A cellular organelle containing enzymes that degrade proteins, lipids and nucleic acids to maintain cellular homeostasis.

cGAS–STING signalling: A pathway activated by cytosolic DNA that induces innate immune responses and modulates autophagy.

Mitophagy: Selective autophagic clearance of damaged mitochondria to prevent accumulation of reactive oxygen species.

Axonal spheroid: A swollen axonal segment containing accumulated organelles and vesicles, often found near protein aggregates in diseased neurons.

Endolysosomal biogenesis: The process by which endosomes mature into lysosomes, enabling degradation of internalised and cytosolic substrates.

References

1. Phospholipase D3 degrades mitochondrial DNA to regulate nucleotide signaling and APP metabolism. Nature Communications (2023).
2. Structural analysis of PLD3 reveals insights into the mechanism of lysosomal 5′ exonuclease-mediated nucleic acid degradation. Nucleic Acids Research (2023).
3. Death-associated protein kinase 1 as a therapeutic target for Alzheimer's disease. Translational Neurodegeneration (2024).
4. Brain somatic mutations observed in Alzheimer’s disease associated with aging and dysregulation of tau phosphorylation. Nature Communications (2019).
5. rs1990622 variant associates with Alzheimer’s disease and regulates TMEM106B expression in human brain tissues. BMC Medicine (2021).
6. PLD3 affects axonal spheroids and network defects in Alzheimer’s disease. Nature (2022).
7. Apolipoprotein E4 and meningeal lymphatics in Alzheimer disease: a conceptual framework. Molecular Psychiatry (2020).