Amyotrophic lateral sclerosis (ALS) is an incurable disease of the
central nervous system. In most cases, ALS is fatal within a short period
following diagnosis. However, people sometimes live with the disease for
decades, as did the astrophysicist Steven Hawking. What happens in the body of
an ALS patient? Muscle movement is controlled by specialised neurons called
motor neurons. During the course of the disease, motor neurons gradually die.
As ALS progresses, patients increasingly suffer from muscle weakness and
paralysis, which leads to speech, movement and swallowing disorders, and severe
restrictions in daily life.
Which processes
lead to neuronal death? This is not yet fully understood, but research has
shown that changes in the behavior of certain proteins are directly related to
ALS. One of these proteins is the RNA-binding protein FUS (Fused in Sarcoma),
which plays a crucial role within cells since it regulates genetic messengers
and participates in the interaction of different proteins. Mutations in FUS
cause FUS to deposit and aggregate in the cytoplasm, causing one of the most
aggressive forms of ALS.
Lara Marrone and
Jared Sterneckert from the Centre for Regenerative Therapies Dresden (CRTD) at
Technische Universität Dresden (TUD), together with collaborating scientists
from Germany, Italy, the Netherlands, and the USA, have now discovered that
interactions between RNA-binding proteins are more critical to ALS pathogenesis
than previously thought. In their recent paper, the research team showed that
impaired FUS protein-protein interactions disrupt the balance (homeostasis) of
RNA-binding proteins, which significantly contributes to the degeneration of
neurons. The scientists also showed that drug-induced protein degradation
(autophagy) reduces the pathological processes linked to aberrantly accumulated
FUS. Stimulating autophagy rescued these RNA-binding proteins and reduced
neuronal death. These improvements were observed in cell culture experiments
with reprogrammed stem cells (iPS cells) from patients and validated using as
the fruit fly as a model organism.
Lara Marrone,
PhD student at the CRTD and lead author of the study, explains: “Mislocalised
FUS overwhelms the protein degradation machinery, causing FUS to accumulate
within the cytoplasm. This triggers a vicious circle that further hampers the
cellular protein quality control systems responsible for the maintenance of
protein homeostasis. This is why we speculated that enhancing autophagy could
also ameliorate the observed RNA-binding phenotypes”. The Sterneckert group
will now investigate the extent to which enhancing autophagy is a possible
therapeutic approach for ALS patients. A further goal of their research is to
use RNA-binding proteins in patient samples as biomarkers for the disease.
The scientists’ results are being reported in the renowned scientific
journal, Acta Neuropathologica. Their research was financed by
TUD / CRTD, the German Research Foundation (DFG), the EU Joint Programme –
Neurodegenerative Disease Research, the Robert Packard Center for ALS Research,
the German Federal Ministry of Education and Research (BMBF), the US National
Institute of Health, the Max Planck Society, the European Research Council, the
Muscular Dystrophy Association, the German Myopathy Society, the Initiative
Therapieforschung ALS e.V., the Petermax-Müller-Stiftung, the Hans and Ilse
Breuer Foundation, and the Humboldt Foundation. It was conducted in cooperation
with universities and research institutes across Europe (Aachen, Amsterdam,
Dresden, Hannover, Milan, Münster) and the US (Pittsburgh, San Francisco). In
addition, it was supported by the Center for Molecular and Cellular
Bioengineering (CMCB) at TUD.
Jared
Sterneckert and his team use induced pluripotent stem cells (iPS cells) to
investigate neurodegenerative diseases, such as ALS and Parkinson’s disease.
They conduct their studies at the CRTD, where top researchers from more than 30
countries are deciphering the principles of cell and tissue regeneration for
disease diagnosis and treatment. The CRTD links the laboratory with the clinic,
connects scientists with physicians, and uses expertise in stem cell research,
genome editing, and tissue regeneration – all for one goal: curing
neurodegenerative diseases such as ALS, Alzheimer’s and Parkinson’s disease,
haematological diseases such as leukaemia, metabolic diseases such as diabetes,
as well as eye and bone diseases, using novel diagnostic tools and therapies.
Journal article: https://link.springer.com/article/10.1007/s00401-019-01998-x
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