Ageing is the set of changes that occur in cells and tissues with increasing age, increasing the risk of disease and death. These changes follow a common programmed sequence and are mainly associated with deterioration of cognitive function and loss of locomotor ability.

These phenomena coincide with the symptoms of neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS), Alzheimer's and Parkinson's, suggesting that these types of diseases share a common molecular basis with the ageing process.

The results of a study investigating the interconnections between ageing and degenerative diseases were recently published in the journal Cell Death and Discovery. The study was coordinated by Fabian Feiguin of the Department of Life and Environmental Sciences at the University of Cagliari and Laura Ciapponi of the Charles Darwin Department of Biology and Biotechnology at Sapienza University of Rome.

The research was funded by Fondazione AriSLA, the main non-profit organisation funding scientific research into ALS in Italy, and AFM-Telethon.

In particular, the study analysed the epigenetic changes that occur with ageing. These are changes in the structure of chromatin, a substance in the cell nucleus made up of DNA and proteins, that affect gene expression, i.e. the process by which the information contained in a gene is translated into a protein without changing the DNA sequence. These changes can alter the expression levels of risk factors for neurodegenerative disease.

"In our study," says Fabian Feiguin from the University of Cagliari, Italy, "we found for the first time that the TDP-43 protein, which plays a central role in the pathogenesis of ALS, gradually reduces its expression as the brains of the common fruit fly (Drosophila melanogaster) and the mouse model age"

The study identified a new role for the enzyme Suv39, which, through the mechanism of methylation, determines the chemical modification of a specific histone protein (the main component of chromatin), affecting the regulation of gene expression.

"Our work," clarifies Marta Marzullo of the Sapienza University team, "has shown that during ageing, both in the fruit fly and the mouse model, the Suv39 methyltransferase acts on the TDP-43 gene, reducing its expression".

"Surprisingly," says Laura Ciapponi of Sapienza, "when we genetically or chemically inactivated Suv39 activity, we observed higher levels of TDP-43 and, above all, a significant reduction in age-related motor decline".

According to the authors, the results of the study therefore identify a novel role for the enzyme Suv39 in the regulation of TDP-43 expression and locomotor senescence and suggest that modulation of the enzyme activities involved in these epigenetic modifications may be a promising approach to understanding and potentially treating age-related neurodegenerative diseases such as ALS.

"We are pleased to have supported this line of research, which has contributed to increasing our knowledge of the molecular mechanisms involved in the pathogenesis of ALS," states Mario Melazzini, President of the Fondazione AriSLA, which co-funded the study. "The importance of conducting studies on the role of TDP-43 has also been recently highlighted by the strategic plan for ALS research of the NINDS (National Institute of Neurological Disorders and Stroke), the main institute of the US NIH for neurological research. In line with this vision, we believe it is strategic to continue to support basic research aimed at providing tangible answers for patients".

References: 

Su(var)3-9 mediates age-dependent increase in H3K9 methylation on TDP-43 promoter triggering neurodegeneration, Marzullo M., Romano G., Pellacani G., Riccardi F., Ciapponi L, e Feiguin F, Su(var)3-9 mediates age-dependent increase in H3K9 methylation on TDP-43 promoter triggering neurodegeneration | Cell Death Discovery (nature.com)

Further Information

Laura Ciapponi
Department of Biology and Biotechnology Charles Darwin
laura.ciapponi@uniroma1.it