Mouse study confirms early inflammation in hereditary paralysis condition

A joint study conducted by the University of Bonn and the Dzne has confirmed an early stage of brain inflammation in mice.

Patients with spastic parapegia Type 15 develop movement disorders during adolescence that ultimately require the use of a wheelchair. In the early stages of this rare hereditary disease, the brain seems to play an important role by activating the immune system, as a recent study published in the Journal of Experimental Medicine. The study was led by researchers from the University of Bonn and the German Center for Neurodegenerative diseases (DZNE). These findings can also be relevant to Alzheimer’s disease and other neurodegenerative disorders.

Spastic parapegia Type 15 is characterized by the progressive loss of neurons in the central nervous system responsible for controlling movement. The first symptoms usually appear in late childhood and first manifest themselves in the legs in the form of uncontrollable muscle twitching and paralysis.

What exactly causes these neurons to die is still not fully understood. In this study we investigated the potential role of the immune system in this process. “

Professor Elvira Mass, Limes Institute, University of Bonn

Professor Mass and Dr. Marc Beyer van de Dzne, together with Professor Ralf Stumm of the University Hospital Jena, served as the main researchers of the study, which brought together extensive experience to study this rare hereditary disease. The situation is activated by a defect in the so-called SPG15 gene, which contains instructions for building a protein. But because of that defect, the protein cannot be produced.

Severe inflammation prior to the start of cell damage

In their experiments, the researchers used mice that shared the same genetic defect. “There was existing evidence that inflammatory processes in the brain play a role in the development of the disease,” Dr. explains. Beyer from, “so we studied microglia, the immune cells of the brain, and also whether immune cells in bone marrow are also involved in the inflammatory reaction.”

White blood cells, which represent an aggregation of various defense cells that are important when combating diseases in the body, form in bone marrow. These cells can reach the brain through the bloodstream. Microglia, on the other hand, has already been migrated to the brain during embryonic development. The researchers managed to specifically label the cells that are derived from bone marrow with a fluorescent dye. “This makes them distinguished from microglia under a microscope,” is mass. “This allowed us to study the interaction between these two cell populations at individual cell level.”

Analyzes show that the microglia cells undergo dramatic changes in very early stages of the disease, long before neuronal damage is identifiable. The cells are therefore changed to “disease-associated microglia.” These release messenger -which, among other things, evoke the help of cytotoxic “killer” t -cells from the bone marrow that destroy other cells. The two cell types communicate with each other through signal molecules and their interplay stimulates the inflammatory process.

Findings open new therapeutic options

“Our data suggests that the early stages of the disease are not powered by the loss of motor neurons, but rather due to the severe, early immune response,” Relates Massa, “and that finding new therapeutic possibilities implies. Immune suppressing medicines may help to delay the progress of the disease.”

Inflammation processes in the brain play an important role in Alzheimer’s and other neurodegenerative diseases. Spastic parapegia is caused by completely different circumstances than dementia, but a very similar disruption of the immune system can be involved in dementia.

The findings are therefore of great importance and come as the fruit of close interdisciplinary cooperation within the ImmunoSensation2 Cluster of Excellence, of which Professor Mass and Dr. Beyer from the Dzne member.

Dr. Beyer emphasizes that “only by combining the sciences of immunology and neurobiology with advanced technology was with one cell, it was possible to shed light on this aspect of the development of spastic parapegia type 15.”

Institutions involved and financing:

The German Center for Neurodegenerative diseases and the universities of Bonn, Jena and Melbourne were the project partners. The research was funded by subsidies from the German Research Foundation (DFG), the Federal Ministry of Education and Research (BMBF) and the European Research Council (ERC).