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
,Huntington’s disease What you can see here is a huge clump of
This is a disease with a genetic cause only. This Huntingtin proteins/aggregates.
disease causes aggregates of Huntingtin
proteins in the basal ganglia, which causes
chorea, an abnormal involuntary movement
disorder, which is caused by overactivity of
dopamine in the areas of the brain that control
movement.
You can see different stages of cell division. The
cell contains an inclusion body, but because there
is only one of these, one of the daughter cells is
cleared from this inclusion body after the cell
division. This process is called mitotic clearance.
This is a reason why it is “good” to put all the
The aggregates form due to lengthy repeats proteins into one big inclusion body instead of
(CAG) in the genes. multiple small ones.
Genetic causes of neurodegeneration But this process does not apply to
Common: neurodegenerative disease, since neurons do not
• Protein misfolding and aggregation divide. So, there is a state of emergency.
• Inadequate protein quality control
• Sporadic and genetic (except HD) What happens after protein aggregation? This
leads to synaptic dysfunction, and therefore
Different: neuronal loss. A way these aggregates destroy
• Protein in aggregates the neurons is by destroying their membranes.
• Subcellular compartment and brain region The brain has protective mechanisms, such as
affected cellular responses to unfolded protein stress, and
• Gain of toxic function/loss of function neuroinflammation.
Fibrils are multiple proteins stacked on each Responses to misfolded protein stress
other. Fibril formation and disease are This process gets activated in response to the
connected, but not quantitatively. accumulation of misfolded proteins, and which
type of response that gets activated is dependent
on the localization of the aggregation. This is also
related to the location where these proteins get
synthesized. These stress responses can take
place in the cytosol, mostly by the heat-shock
proteins or in the ER, by the unfolded protein
response (UPR, proteasomes, and lysosomes).
Both these responses are only transient, and are
only intended to restore protein folding
homeostasis, but when this does not work, the
stress response becomes part of the disease.
Hsf1 is present in the cytosol, and
The size of these proteins that are stacked on is complexed with chaperones, such
each other does not correlate with the severity as hsp70, and hsp90. When this
of the disease. Research has shown that small complex binds to a misfolded protein
oligomeric species are the most toxic. it cannot trimerize. So, when hsf1
Inclusion bodies are large clumps of protein binds to hsp70, it keeps the protein
aggregates (proteins that are stacked on each in an inactive state. When there is an
other. Since small aggregates are toxic, it accumulation of unfolded proteins, then hsp70
might be a safer way to clump all the proteins binds to these proteins instead of to hsf1, which
together to maybe protect the cell. causes hsf1 to trimerize, and upregulate
transcription of chaperones, and ubiquitin.
, There is also a stress response in the ER. In the Microglia are involved in Alzheimer’s disease. In
membrane of the ER are three proteins for this picture you can see an amyloid plaque in red,
hsf1. These proteins are bound by an hsp70 the microglia are brown. Around the plaque, you
chaperone, which is called BiP. So, hsp70 keeps can see that they are more round, which means
these 3 stress sensors inactive, but when there they are activated. What these microglia are
is an accumulation, BiP is dissociating and trying to do is trying to phagocytose the plaque.
binds to these unfolded proteins. This means
that the sensors are activated, which activates
the unfolded protein response (UPR). 3
pathways can be activated this way.
Triggers for this activation are damaged neurons,
neuronal degeneration, viruses/bacteria, dead
cells/debris, CNS toxins, but also activated
astrocytes. After a while, the inflammation
becomes chronic which increases
proinflammatory cytokines, and ROS production,
Neuroinflammation and impairs phagocytosis. Also, the microglia are
Inflammation is a biological response to defend overactive and start damaging the neurons.
or repair degenerative changes, by eliminating Microglia are activated by a process called
or neutralizing intruding elements. Two types priming. A study showed that microglia get
of cells mediate the inflammatory response in primed with age.
the neurons, microglia, and astrocytes. When
they become activated, they change in
morphology and start to secrete molecules,
such as cytokines into the cell, and start to
phagocytose material.
Astrocytes have a
Defensive reaction
Aiming at handling
Of acute stress,
Limiting tissue Learning objectives
Damage, and • Understands and can describe the involvement
Restoring homeostasis. of protein misfolding/aggregation (oligomers/
In severe astrogliosis the astrocytes can form a fibrils, localisation, and ethiology)
barrier around the damaged tissue, this is • Understands and can describe key pathways in
called an astrocytic scar. protein quality control (chaperones, ubiquitin,
proteasome, and autophagy)
• Understands the mechanism of proteostatic
stress responses (heat-shock response, unfolded
protein response)
• Understands the involvement of the
neuroinflammatory response
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
,Huntington’s disease What you can see here is a huge clump of
This is a disease with a genetic cause only. This Huntingtin proteins/aggregates.
disease causes aggregates of Huntingtin
proteins in the basal ganglia, which causes
chorea, an abnormal involuntary movement
disorder, which is caused by overactivity of
dopamine in the areas of the brain that control
movement.
You can see different stages of cell division. The
cell contains an inclusion body, but because there
is only one of these, one of the daughter cells is
cleared from this inclusion body after the cell
division. This process is called mitotic clearance.
This is a reason why it is “good” to put all the
The aggregates form due to lengthy repeats proteins into one big inclusion body instead of
(CAG) in the genes. multiple small ones.
Genetic causes of neurodegeneration But this process does not apply to
Common: neurodegenerative disease, since neurons do not
• Protein misfolding and aggregation divide. So, there is a state of emergency.
• Inadequate protein quality control
• Sporadic and genetic (except HD) What happens after protein aggregation? This
leads to synaptic dysfunction, and therefore
Different: neuronal loss. A way these aggregates destroy
• Protein in aggregates the neurons is by destroying their membranes.
• Subcellular compartment and brain region The brain has protective mechanisms, such as
affected cellular responses to unfolded protein stress, and
• Gain of toxic function/loss of function neuroinflammation.
Fibrils are multiple proteins stacked on each Responses to misfolded protein stress
other. Fibril formation and disease are This process gets activated in response to the
connected, but not quantitatively. accumulation of misfolded proteins, and which
type of response that gets activated is dependent
on the localization of the aggregation. This is also
related to the location where these proteins get
synthesized. These stress responses can take
place in the cytosol, mostly by the heat-shock
proteins or in the ER, by the unfolded protein
response (UPR, proteasomes, and lysosomes).
Both these responses are only transient, and are
only intended to restore protein folding
homeostasis, but when this does not work, the
stress response becomes part of the disease.
Hsf1 is present in the cytosol, and
The size of these proteins that are stacked on is complexed with chaperones, such
each other does not correlate with the severity as hsp70, and hsp90. When this
of the disease. Research has shown that small complex binds to a misfolded protein
oligomeric species are the most toxic. it cannot trimerize. So, when hsf1
Inclusion bodies are large clumps of protein binds to hsp70, it keeps the protein
aggregates (proteins that are stacked on each in an inactive state. When there is an
other. Since small aggregates are toxic, it accumulation of unfolded proteins, then hsp70
might be a safer way to clump all the proteins binds to these proteins instead of to hsf1, which
together to maybe protect the cell. causes hsf1 to trimerize, and upregulate
transcription of chaperones, and ubiquitin.
, There is also a stress response in the ER. In the Microglia are involved in Alzheimer’s disease. In
membrane of the ER are three proteins for this picture you can see an amyloid plaque in red,
hsf1. These proteins are bound by an hsp70 the microglia are brown. Around the plaque, you
chaperone, which is called BiP. So, hsp70 keeps can see that they are more round, which means
these 3 stress sensors inactive, but when there they are activated. What these microglia are
is an accumulation, BiP is dissociating and trying to do is trying to phagocytose the plaque.
binds to these unfolded proteins. This means
that the sensors are activated, which activates
the unfolded protein response (UPR). 3
pathways can be activated this way.
Triggers for this activation are damaged neurons,
neuronal degeneration, viruses/bacteria, dead
cells/debris, CNS toxins, but also activated
astrocytes. After a while, the inflammation
becomes chronic which increases
proinflammatory cytokines, and ROS production,
Neuroinflammation and impairs phagocytosis. Also, the microglia are
Inflammation is a biological response to defend overactive and start damaging the neurons.
or repair degenerative changes, by eliminating Microglia are activated by a process called
or neutralizing intruding elements. Two types priming. A study showed that microglia get
of cells mediate the inflammatory response in primed with age.
the neurons, microglia, and astrocytes. When
they become activated, they change in
morphology and start to secrete molecules,
such as cytokines into the cell, and start to
phagocytose material.
Astrocytes have a
Defensive reaction
Aiming at handling
Of acute stress,
Limiting tissue Learning objectives
Damage, and • Understands and can describe the involvement
Restoring homeostasis. of protein misfolding/aggregation (oligomers/
In severe astrogliosis the astrocytes can form a fibrils, localisation, and ethiology)
barrier around the damaged tissue, this is • Understands and can describe key pathways in
called an astrocytic scar. protein quality control (chaperones, ubiquitin,
proteasome, and autophagy)
• Understands the mechanism of proteostatic
stress responses (heat-shock response, unfolded
protein response)
• Understands the involvement of the
neuroinflammatory response
