A factor that could support the early detection of neurodegenerative diseases such as Alzheimer’s or Parkinson’s has been identified by researchers at the University of Basel. This cytokine, Known as Fgf21, is induced by cellular stress reactions after disturbances of the mitochondria.

The normal functioning of human cells is based on the coordinated interaction of different cellular organelles. In many cases, impaired communication between these organelles will lead to the activation of a stress response to ensure the survival of affected cells.

A research group was able to demonstrate this in detail for brain neurons. The group is headed by Prof. Dr. Stephan Frank from the Institute of Medical Genetics and Pathology at the University of Basel and University Hospital of Basel; the universities of Cambridge (UK) and Padua (Italy) were also involved.

Neuronal Expression Of FGF21

The neuropathologists were able to show that impairments on the level of mitochondria also affect neighboring organelles, such as the so-called endoplasmic reticulum. A consecutively activated stress reaction leads to the release of fibroblast growth factor 21 (FGF21) by nerve cells with disturbed mitochondria.

The Basel researchers further observed that the same substance is also induced in various models of neurodegenerative disorders, where it can be detected prior to neuronal cell death.

As chronic cell stress is an important factor in the development of neurodegenerative diseases, FGF21 could potentially be suitable as a biomarker for the pre-symptomatic detection of diseases such as Alzheimer’s or Parkinson’s. However, as FGF21 can also be produced by other tissues and organs, such as adipose tissue and the liver, further rigorous testing will be required in this regard.

Biomarker Needed

The availability of a robust biomarker would represent an important advance in the development of novel approaches targeting chronic cell stress to provide neuroprotection.

The work took advantage of a mouse model of mitochondrial fission in forebrain neurons which the group had previously developed.  The results demonstrate that neurons sense dysregulated mitochondrial dynamics and endoplasmic reticulum stress to trigger a complex stress response leading to release of the cytokine Fgf21.

The research was supported by the SNSF, Novartis Foundation for Medical-Biological Research, Desiree and Nils Yde Foundation, Bangerter-Rhyner Foundation, Nora van Meeuwen-Haefliger Foundation, Mach-Gaensslen Foundation, Forschungsfonds of Basel University; ERC, MRC, Alzheimer’s Society, ARUK/DRI, Telethon Italy, AIRC Italy, ERC ERMITO, CristOpa, and MIUR FIRB Automed.

Restelli et al. Neuronal Mitochondrial Dysfunction Activates the Integrated Stress Response to Induce Fibroblast Growth Factor 21 Cell Reports 24, 1407–1414 August 7, 2018

Image: Wellcome Images

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