Potential Breakthrough in Dementia Treatment: Restoring Genetic Messaging in Neurons Using Clinical-Stage Drugs

Recent research from the Francis Crick Institute and UCL has revealed that in neurodegenerative diseases like Alzheimer's and frontotemporal dementia (FTD), the genetic instructions within nerve cells become misplaced, disrupting cellular functions crucial for energy production. This mislocalization predominantly affects messenger RNAs (mRNAs) that regulate mitochondrial activity, which are essential for maintaining healthy brain cells.

The scientists used skin cells from individuals with inherited forms of Alzheimer's and FTD, which carry mutations in genes such as APP, PSEN1 (Alzheimer’s), and VCP (FTD). These cells were reprogrammed into stem cells and differentiated into cortical neurons, enabling detailed examination of mRNA localization. They discovered that in healthy neurons, over 4,000 mRNAs are correctly positioned, but in affected neurons, 82 to 140 mRNAs are abnormally located, often near the nucleus or in the cytoplasm. Notably, ten mRNAs common to both diseases carried messages related to mitochondrial function, with nine shifted to the cytoplasm and one to the nucleus.

Further analysis of postmortem brain tissue from 40 FTD patients and 49 controls demonstrated that several of these misplaced mRNAs correlated with disease severity, making them potential biomarkers.

The study also uncovered that mitochondrial DNA (mtDNA) leaks into the cell’s cytoplasm, accompanied by a reduction in mitochondrial number and size, impairing energy production. This leakage also activates inflammatory pathways, which could contribute to neurodegeneration.

Importantly, the researchers tested a drug called ML240, which inhibits a protein named VCP involved in cellular protein processing. Treatment restored the normal localization of mRNAs, reduced mitochondrial DNA leakage, dampened inflammation, and improved mitochondrial function. These promising findings suggest that targeting VCP could be a novel therapeutic strategy.

Christy Hung emphasized that this phenomenon of genetic message misplacement may be a universal feature across various neurodegenerative conditions, with mitochondrial DNA leakage potentially driving inflammation and disease progression. As Rickie Patani highlighted, understanding this mechanism opens new avenues for therapeutic development and warrants further testing in model organisms.