MPBD: Neurodegenerative Diseases
Neurodegeneration means the loss of brain But what if the chaperones fail? Incorrectly
cells, and therefore brain function. folded proteins receive a ubiquitin tag that marks
them for degradation by the proteasome.
The proteasome recognizes the ubiquitin tag. The
proteasome consists of a catalytic chamber with
proteolytic acids that can degrade the proteins.
But when a protein is already aggregated, it
cannot enter the chamber. Reduced proteasome
activity is also seen in neurodegenerative
diseases. Autophagy by lysosomes is also
involved in degradation. It for example degrades
All diseases are associated with different brain proteins, nucleic acids, and mitochondria. If
areas. In all these diseases protein aggregates these systems don’t work, there is an
form. These are not properly folded proteins accumulation of ubiquitinated proteins.
that expose certain areas that are normally on
the inside of a protein. These areas are very
sticky and can clump together to form
aggregates, such as amyloid fibres. This
aggregation leads to loss of protein function or
toxicity. Protein quality control is a process
that tries to prevent this aggregate formation
from happening.
Proteins are synthesized on ribosomes in
different parts of the cell, either the cytosol or
the endoplasmatic reticulum. The ER
synthesizes secretion proteins,
transmembrane proteins or organelle-targeted
proteins. After translation proteins need to be But why does this aggregation happen?
folded in a functional conformation. This is Sometimes there is an overexpression of proteins
done by chaperones, also called heat-shock that causes it to accumulate. Sometimes there is
proteins (HSP) that bind to the proteins. These a mutation in the protein, but also cellular stress
chaperones facilitate protein folding and and ageing contribute to the formation of
refolding by keeping proteins in a “folding- aggregates.
competent state”. There are different classes of
heat-shock proteins, ATP-dependent (hsp90,
hsp70, and hsp60), and ATP-independent
(small HSP).
Hsp70 cycle
The binding and release of the substrate are
dependent on co-chaperone and ATP. Hsp70
can recognize hydrophobic amino acids on a
protein's surface. Aided by a set of other Etiology of neurodegenerative diseases
proteins, ATP-bound hsp70 molecules grasp • Sporadic (most of the time it occurs without a
their target protein and hydrolyze ATP to ADP, particular reason).
undergoing conformational changes that cause • Acquired (physically given)
the hsp70 molecules to bind more tightly with • Genetic (mutations in the genes that encode for
the target. After the other protein dissociates, the main component of the aggregate, this can be
the rebinding of ATP induces the dissociation a missense or deletion).
of hsp7O after ADP release. Repeated cycles of
HISP binding and release help the target https://www.youtube.com/watch?
protein to refold. v=HBLrY_nXU_U
Neurodegeneration means the loss of brain But what if the chaperones fail? Incorrectly
cells, and therefore brain function. folded proteins receive a ubiquitin tag that marks
them for degradation by the proteasome.
The proteasome recognizes the ubiquitin tag. The
proteasome consists of a catalytic chamber with
proteolytic acids that can degrade the proteins.
But when a protein is already aggregated, it
cannot enter the chamber. Reduced proteasome
activity is also seen in neurodegenerative
diseases. Autophagy by lysosomes is also
involved in degradation. It for example degrades
All diseases are associated with different brain proteins, nucleic acids, and mitochondria. If
areas. In all these diseases protein aggregates these systems don’t work, there is an
form. These are not properly folded proteins accumulation of ubiquitinated proteins.
that expose certain areas that are normally on
the inside of a protein. These areas are very
sticky and can clump together to form
aggregates, such as amyloid fibres. This
aggregation leads to loss of protein function or
toxicity. Protein quality control is a process
that tries to prevent this aggregate formation
from happening.
Proteins are synthesized on ribosomes in
different parts of the cell, either the cytosol or
the endoplasmatic reticulum. The ER
synthesizes secretion proteins,
transmembrane proteins or organelle-targeted
proteins. After translation proteins need to be But why does this aggregation happen?
folded in a functional conformation. This is Sometimes there is an overexpression of proteins
done by chaperones, also called heat-shock that causes it to accumulate. Sometimes there is
proteins (HSP) that bind to the proteins. These a mutation in the protein, but also cellular stress
chaperones facilitate protein folding and and ageing contribute to the formation of
refolding by keeping proteins in a “folding- aggregates.
competent state”. There are different classes of
heat-shock proteins, ATP-dependent (hsp90,
hsp70, and hsp60), and ATP-independent
(small HSP).
Hsp70 cycle
The binding and release of the substrate are
dependent on co-chaperone and ATP. Hsp70
can recognize hydrophobic amino acids on a
protein's surface. Aided by a set of other Etiology of neurodegenerative diseases
proteins, ATP-bound hsp70 molecules grasp • Sporadic (most of the time it occurs without a
their target protein and hydrolyze ATP to ADP, particular reason).
undergoing conformational changes that cause • Acquired (physically given)
the hsp70 molecules to bind more tightly with • Genetic (mutations in the genes that encode for
the target. After the other protein dissociates, the main component of the aggregate, this can be
the rebinding of ATP induces the dissociation a missense or deletion).
of hsp7O after ADP release. Repeated cycles of
HISP binding and release help the target https://www.youtube.com/watch?
protein to refold. v=HBLrY_nXU_U
