Mainz University. Germany: Neurodegenerative disorders such as Alzheimer's disease are typically
characterized by protein deposits in the brain. These are comprised of
defective, insoluble proteins which no longer fulfill their function and
which cells are unable to break down. The work group headed by
Professor Christian Behl of the Institute of Pathobiochemistry of the
University Medical Center of Johannes Gutenberg University Mainz has
determined the RAB3GAP complex as a novel factor that influences the
efficient degradation of proteins.
The researchers were able to show
that the complex plays an important role in autophagy, a physiological
process that breaks down cellular proteins and organelles. This insight
opens up possible new options for the development of therapeutic and
preventative approaches for neurodegenerative diseases. The work group
has published the results of their research in the specialized journal Autophagy.
The team led by Professor Christian Behl and Dr.
Andreas Kern showed that the RAB3GAP complex has a decisive influence
on the process of protein degradation and represents an important
element of the cellular autophagy network. Autophagy is a process in
which cells digest their own components. These could be excessive or
damaged organelles, such as mitochondria, invading pathogens, such as
viruses or bacteria, or cytoplasmic macromolecules. Autophagy serves on
the one hand for the recycling of the building blocks of cells and the
provision of energy, but is also activated specifically in stress
situations. "The controlled protein degradation by autophagy is a core
aspect of protein homoeostasis, which means the complex interplay
between the formation, folding, and decomposition of proteins. We have
extended our understanding of age-related disorders by identifying new
factors involved in this process," said Professor Christian Behl.
The research group discovered that the RAB3GAP
complex promotes the formation of autophagic vesicles. These are
bubble-like structures with a lipid shell that envelop the substrates to
be degraded. The autophagic vesicles then fuse with lysosomes, simple
cell organelles, which contain digestive enzymes that break down the
substrates into their component parts. "The autophagic vesicles need
lipid membranes to form, and the cell has to provide those. Our
discovery suggests that RAB3GAP recruits the lipids required for the
autophagic degradation of proteins," explained Dr. Andreas Kern of the
Institute of Pathobiochemistry, who was responsible for the experiments.
It was previously known that the RAB3GAP complex is important for the
regulation of the RAB GTPase RAB3, and that it influenced vesicle
transport at the synapses, which are the contact points between nerve
cells. The novel finding established that the complex indeed has a dual
function, which is of particular relevance with regard to diseases of
the nervous system.
The researchers made their discovery employing the nematode C. elegans, which serves as a simplified model, to study the human nervous system. In C. elegans,
the biochemists were able to knock down approximately 2,500 individual
genes using special molecular biological techniques and analyze the
effects on protein aggregation. This allowed the identification of
numerous genes that were associated with increased protein aggregation
once they had been turned off. Subsequently, the precise functional
characterization was completed using cultures of human cells.
The work group at the Institute of
Pathobiochemistry was also able to demonstrate that the positive
influence on autophagy by the RAB3GAP complex antagonizes that of a
previously known negative autophagy regulator. "Our hypothesis is that
it is the relative balance of the effects of these opposed molecules
that determines the overall autophagic activity of cells. We believe
that not only have we come closer to understand the autophagy process
itself but also, and more importantly, that it may be possible to
develop new approaches to the treatment and prevention of
neurodegenerative diseases by means of targeted intervention in this
process," stated Behl.
In addition to the Mainz-based team, biochemists
from Goethe University Frankfurt am Main were also involved in the
research project that stretched over several years. This received
funding from a wide range of organizations, including the Alzheimer
Forschung Initiative e.V., the German Research Foundation (DFG) – also
within the framework of the Collaborative Research Center 1080:
"Molecular and cellular mechanisms of neural homoeostasis" –, the
European Research Council (ERC), and a number of foundations.