Shedding light on a neurodegenerative disease most often of unknown origin

Deciphering genetic diseases is a giant step towards the development of treatments. The Genetics of Neurodevelopmental Disorders Lab has just discovered that mutations in the MINPP1 gene could cause pontocerebellar hypoplasia, a neurodegenerative disease of young children. Explanation with Vincent Cantagrel, director of this laboratory.

Published on 02.12.2020

Research Acceleration

You have just demonstrated the involvement of the MINPP1 gene in the occurrence of a neurodegenerative disease, what are the characteristics of this disease? 

Vincent Cantagrel

Vincent Cantagrel: This disease, called pontocerebellar hypoplasia, belongs to a group of very rare but extremely severe neurological disorders. Affected children present signs of neurodegeneration occurring so early that it affects the development of the brain. The posterior part of the brain, the cerebellum is specially affected. The cognitive and motor development of these children is highly impacted and most of them die during childhood. Unfortunately, there is no treatment and for more than a third of the affected children, the genetic cause of the disease is not known.

We investigated the cases without genetic diagnosis and found that some of them have inactivating mutations in a gene called MINPP1.


How does this gene act at the level of neurons?

V. C. :The product of the MINPP1 gene is responsible for the degradation of the phytic acid, a substance very well known in plants. In plant seeds, it is used as an energy store for phosphorous and metal ions such as magnesium, iron and calcium. However, a specific role for this phytic acid inside human cells and during brain development was totally unknown.

To understand the role of this phytic acid and the MINPP1 gene in neural cells, we used skin cells from patients that we converted into stem cells and then into neurons, to mimic neurodevelopment and neuronal birth. The analysis of the content of these cells revealed a strong accumulation of phytic acid. Surprisingly, we also observed that the cells from patients were very slow to produce neurons and that they die often during the process.

So, the accumulation of this phytic acid is likely to be toxic for these cells and MINPP1 would play an essential role in preventing this toxicity during the genesis of neurons. How this phytic acid could be toxic in the cells and in the brain was a mystery.


What is the function of this mechanism in the brain? And in the organism?

V. C. : We studied diverse cell types with inactivating mutation of MINPP1 to understand the consequences of the accumulation of the phytic acid. As this compound is known to bind metal ions, we studied how these metal ions could be affected in mutant cells. We were extremely surprised to see that iron or calcium were completely disturbed in presence of the toxic accumulation. Our results show that the phytic acid, in patients' cells is acting like a “magnet” that “rob” available iron of calcium and prevent the cells to use them. Calcium is known to play key roles on the differentiation of neurons, such depletion is expected to be very deleterious for the cell. This phenomenon explains why the cells dye and the degeneration occurs in the brain.


Which patients could benefit from this work and how?

V. C. : This work is the very first study to describe this defect but we can now identify more quickly patients with mutations in the MINPP1 gene and provide them a molecular diagnosis. Concerning treatments, there is now a target in this disease, the toxic accumulation of this compound that should be stopped. Although there are no obvious pharmacological options available, it is a starting point to investigate.


Who were the people involved as well as the partners?

V. C. : Our neuroradiologist, Pr. Nathalie Boddaert, who is also in charge of a research laboratory at Imagine, played a key role at the beginning of the study, when it was still difficult to consider this gene as a good candidate for the disease. She compared the brain MRI of the patients and identified a similar pattern that is not seen usually in this type of disease and that was observed only in presence of MINPP1 mutations. This observation suggested that MINPP1 mutations cause a specific syndrome that can be recognized with brain imaging. This work was possible thanks to the involvement of a specialist of this phytic acid and its biosynthesis, Pr. Adolfo Saiardi who is at UCL in London. Several groups played an important role specially clinicians who identified additional patients. Overall, it was great to see that the vast majority of the experimental work was possible thanks to people in the lab, mostly Ekin Ucuncu (PhD student) and Karthi Rajamani (a postdoc researcher) as well as many platforms inside Imagine. 


What will be the next step?

V. C. : Interestingly, the brain damage of the MINPP1 patients has some similarities with other neurodegenerative disorders presenting metal accumulation in the brain. A link with these other neurodegenerative diseases could be interesting to investigate.  There is also some important work to do specially with a mouse model to understand better how the brain development is impaired.



MINPP1 prevents intracellular accumulation of the chelator inositol hexakisphosphate and is mutated in Pontocerebellar Hypoplasia

Ekin Ucuncu et al.

Nature communications