Huntington's Disease (HD) is classified as a neurodegenerative by vyo46383

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									Rachel Fernandez
Molecule to Organism
Cell Signaling
Nancy Murray




                                Huntington’s Disease
                       An Inherited Neurodegenerative Disease



Overview
Huntington’s Disease (HD) is classified as a fatal, neurodegenerative disorder responsible
for the rapid, apoptotic death of the striatal neurons found primarily in the basal ganglia.
HD is an autosomal, dominant hereditary disease that potentially affects 50% of offspring
due to the mutant allele containing the huntingtin gene. This gene encodes the mutant
huntingtin protein which contains a multitude of CAG repeats within the pathogenic
range of 40 or more, known as the polyglutamine tract. The disease usually manifests
during adulthood; however, there have been some cases of children being afflicted when
there exists an amount of glutamine repeats exceeding one-hundred. Several theories
attempting to explain the abnormal properties in HD have arisen since the discovery of
the mutant gene in 1993. However, the exact mechanism implicated in this neuronal cell
death has yet to be determined, and consequently the pathology of HD has remained at
the forefront of molecular genetics. Thus far HD research has been able to establish that
the aberrant misfolding of the synthesized huntingtin protein leads to the formation of
aggregates (as in Alzheimer’s Disease) which mediates the apoptotic pathway within the
striatal neurons.

History

Although HD traits have been traced to the Middle Ages, a physician George Huntington
first characterized Huntington’s disease in 1872. He recorded the physical features of the
disease, like the uncontrollable, dance-like movements known as chorea. In addition, he
noted the array of emotional and cognitive debilitations as well as its progressive, and
ultimately fatal nature. It was not until 1955 that a young doctor named Amerigo
Negrette arrived in a small fishing village, San Luis, Venezuela, to discover that many of
its inhabitants exhibited uncoordinated motor skills reminiscent of HD. He realized that
they had a familial disorder referred to as el Mal de San Vito, and he decided to study the
largest known population of HD patients. Years later, through the DNA samples of the
villagers, the huntingtin (IT-15) gene was detected on chromosome 4 of the human
genome.
Pathology of Huntington’s Disease

The pathology of HD exists in the progressive loss of striatal neurons causing acute
dysfunction of the basal ganglia region, particularly the striatum. Due to the fact that this
area of the brain controls motor control, cognition, and sensory pathways, levels of
dopamine are a key factor in the clinical symptoms of HD. In addition, the vast majority
of the striatal neuron population consists of (g-aminobutyric acid) GABA-containing
spiny striatal neurons. Since the GABA hormone acts as a dopamine level regulator, the
death of GABA-containing neurons will eventually result in an accumulation of
dopamine. This overproduction of dopamine can be visualized in HD patients in the
form of increased, random movement during the early stages of the disorder. In fact,
James A. Bibb and colleagues performed a study on transgenic mice that express the
human huntingtin. They were able to show that the presymptomatic mice had severe
deficiencies in dopamine signaling within the striatum (2000). As the disease progresses
the natural dopamine levels are depleted leading to rigid movements and tremors, as in
Parkinson’s Disease.

It is believed that the monitoring mechanism during the protein synthesis of the mutant
huntingtin malfunctions, leading to an abnormal protein conformation. Researchers
contend that the exposed hydrophobic amino acid regions interact with one another to
cause protein misfolding. Since the protein quality control system cannot function
normally any misfolded proteins synthesized will not be degraded and recycled properly;
therefore, they will accumulate inside the neuronal cells, both internuclear and
cytoplasmic. Eventually the aberrant protein particles assemble into a more structured,
ordered -sheet arrangement of fibrils known as amyloids. Toxic oligomer molecules
serve as intermediate building blocks during this fibril formation. An amyloid-like,
transmembrane complex, the GST/huntingtin fusion, undergoes proteolytic cleavage,
causing an excessive accumulation of fragments which form aggregates, often described
as amyloid deposits.

The formation of these aggregates can take years or decades. It was originally held by
some researchers that these aggregates represented a ―black hole‖ to other healthy
proteins, thereby becoming irreversibly trapped. Although this is true to some extent,
researchers at Northwestern University were able to ascertain the role of the molecular
chaperone, Hsp70, in minimizing the aggregate’s toxic effect on the striatal neurons.
Soojin Kim and researchers filmed, using fluorescence imaging, normal proteins entering
and detaching from the HD aggregate without any fluorescence showing. This serves as
a strong indicator that some other protein must ―chaperone‖ these healthy proteins
through the aggregates, cleaning up any damage that may occur and escorting them out
unscathed (2002). With the aid of the molecular chaperones, exponential aggregate
growth may be minimized, therefore prolonging the life of a neuron as well as the patient.
Cell Signaling Pathway Involved

Apoptosis can occur in an extrinsic as well as an intrinsic pathway. It is believed that
both routes are utilized during the neuronal cell death in HD. Ivelisse Sanchez proposes
an extrinsic mechanism for striatal cell death. The Fas ligand on a ―killer cell‖ interacts
with the Fas Associated Death Domain (FADD) of the target cell. FADD acts as an
adaptor protein which aids in the binding of Caspase-8 to form a complete complex. This
Fas/FADD/Caspase-8 complex cooperates with the aggregates to initiate a caspase
cascade of events that is essential in apoptotic neuron death (2000).

A secondary apoptotic pathway involves the mitochondria when there is enough ATP
available. Normally, the mitochondria stores Ca² and conducts calcium homeostasis ;
however, the HD mitochondria undergoes excessive accumulation of Ca², causing
mitochondrial swelling and the release of cytochrome c. Cytochrome c interacts with an
adaptor protein, Apaf-1, to enable the conformational binding of Caspase-9. The caspase
cascade ensues, the DNA is fragmented, and the neuron dies.

The nexus between aggregate formation and the death of the neurons remains to be
understood. Unlike Sanchez, Frederic Saudou proposes that HD acts within the nucleus
to induce apoptosis, but cell death does not correlate with the formation of intranuclear
aggregates (1998). In other words, cell death is dependent upon the presence of
aggregates, but these toxic fragments do not necessarily cause apoptosis.


Theories for Neuronal Cell Death in Huntington’s Disease

Several theories have surfaced in attempt to explain the pathogenic apoptotic mechanism
occurring in Huntington’s disease. One in particular, associates the excitotoxicity and
subsequent mitochondrial dysfunction within the neurons as a means for apoptosis.
Excitotoxicity involves the overstimulation of NMDA glutamate receptors.
Consequently, neuronal cells die due to this excessive excitatory amino acid
neurotransmission. When an NMDA-agonist is injected into the striatum region of the
brain, the pathology of HD is mimicked.

The HD mitochondria suffers from ATP depletion and therefore disrupts the Na/K pump
activity which maintains the resting membrane potential of the neuron. As a result, the
Mg² blockade of the voltage-dependent, N-methyl-d-aspartate (NMDA) glutamate
receptors is diminished. This, in turn, allows greater affinity of the excessive glutamate
to the unobstructed NMDA receptors. This overabundance of NMDA receptor activation
leads to a toxic influx of Ca² into the mitochondria, triggering swelling. This may be a
mechanism for the release of cytochrome c during apoptosis. The fact that a normal
mitochondria can be induced to behave similarly to an HD mitochondria when it is
incubated in polyglutamine repeats suggestive of the mutant huntingtin protein provides
sufficient support for this hypothesis.
Treatment Options

Since not much is known about the disease mechanism itself, treatment options have been
confined to symptomatic therapies that may mask the disease, but by no means stops its
progression. Drugs that inhibit glutamate neurotransmission can alleviate the risk of
excitotoxicity. Remacemide can block NMDA receptors and medications, such as
Rilutek inhibit the synthesis of glutamate itself. Another means to reverse the
mitochondrial malfunction includes calcium channel blockers and inhibitors of nitric
oxide synthetase (NOS), a calcium-activated enzyme. Some neurological procedures that
can alter the effects of motor dysfuntion in other neurodegenerative disorders, such as
Parkinson’s disease, could potentially be applied to HD patients.
Other more controversial treatment options exist to restore loss of function in neurons.
The fetal brain tissue transplantation procedure extracts striatum tissue from an electively
aborted fetus and transplants the tissue into a deceased region of the brain in an HD
patient. Not many cases have undergone this procedure to assess its real therapeutic
value; nonetheless, it has been reported that the transplantation has ceased the
progression of HD and reversed some of the neuronal damage.




References



Bibb, J., Yan, Z. ―Severe deficiencies in Dopamine Signaling in presymptomatic
Huntington’s Disease
        Mice‖ Molecular Phys., Yale University School of Medicine (2002).

Dalke, K. ―Movies Capture Proteins on the Move in Brain Disease‖ Genome News
Network (2003).

Kim, S., et al. (2002). Polyglutamine protein aggregates are dynamic. Nat. Cell Biol.,
4:826-31.

Max Planck Institute for Molecular Genetics Berlin. ―Molecular Analysis of
Huntington’s Disease.‖

Miyashita, T., Ohtsuka, Y. (2001) Extended Polyglutamine selectively interacts with
Caspase-8 and –10 in
      nuclear aggregates. Cell Death and Differentiation, 8:377-86.

Muchowski, P. ―Molecular and Cellular Basis of Chaperone Function and Protein
Misfolding Diseases‖
       University of Washington Department of Pharmacology.
National Institute of Neurological Disorders. ―Huntington’s Disease—Hope Through
Research.‖

Nijhawan, D., Honarpour, N. (2000) Apoptosis in Neural Development and Disease.
Ann. Rev. Neuosci.,
      23:7387.

Palmer. M., Greengrass, P.M. (2000). The Role of the Mitochondria in Apoptosis. Drug
News nd
       Perspectives, 13:378-84.

Sangaramoorthy, M. ―Linking Brain and Behavior: Reflections on Neurodegenerative
Disease and Fetal
       Neural Transplantation.‖ (1998).

Saudou, F., et al. (1998) Cell Death in Huntington’s Disease Does Not Correlate with
Inclusions. Cell,
        95:55-56.

Schulz, J.B., Nicotera, P. (2000) Targeted Modulation of Neuronal Apoptosis: A
Double-Edged Sword.
       Brain Pathology, 10:273.
The formation of these aggregates can take years or decades. It was originally held by
some researchers that these aggregates represented a ―black hole‖ to other healthy
proteins, thereby becoming irreversibly trapped. Although this is true to some extent,
researchers at Northwestern University were able to ascertain the role of the molecular
chaperone, Hsp70, in minimizing the aggregate’s toxic effect on the striatal neurons.
Soojin Kim and researchers filmed, using fluorescence imaging, normal proteins entering
and detaching from the HD aggregate without any fluorescence showing. This serves as
a strong indicator that some other protein must ―chaperone‖ these healthy proteins
through the aggregates, cleaning up any damage that may occur and escorting them out
unscathed (2002). With the aid of the molecular chaperones, exponential aggregate
growth may be minimized, therefore prolonging the life of a neuron as well as the patient.



Apoptosis can occur in an extrinsic as well as an intrinsic pathway. It is believed that
both routes are utilized during the neuronal cell death in HD. Ivelisse Sanchez proposes
an extrinsic mechanism for striatal cell death. The Fas ligand on a ―killer cell‖ interacts
with the Fas Associated Death Domain (FADD) of the target cell. FADD acts as an
adaptor protein which aids in the binding of Caspase-8 to form a complete complex. This
Fas/FADD/Caspase-8 complex cooperates with the aggregates to initiate a caspase
cascade of events that is essential in apoptotic neuron death (2000)??

A secondary apoptotic pathway involves the mitochondria when there is enough ATP
available. Normally, the mitochondria stores Ca² and conducts calcium homeostasis ;
however, the HD mitochondria undergoes excessive accumulation of Ca², causing
mitochondrial swelling and the release of cytochrome c. Cytochrome c interacts with an
adaptor protein, Apaf-1, to enable the conformational binding of Caspase-9. The caspase
cascade ensues, the DNA is fragmented, and the neuron dies.


Several theories have surfaced in attempt to explain the pathogenic apoptotic mechanism
occurring in Huntington’s disease. One in particular, associates the excitotoxicity and
subsequent mitochondrial dysfunction within the neurons as a means for apoptosis.
Excitotoxicity involves the overstimulation of NMDA glutamate receptors.
Consequently, neuronal cells die due to this excessive excitatory amino acid
neurotransmission. When an NMDA-agonist is injected into the striatum region of the
brain, the pathology of HD is mimicked.

        The HD mitochondria suffers from ATP depletion and therefore disrupts the Na/K
pump activity which maintains the resting membrane potential of the neuron. As a result,
the Mg² blockade of the voltage-dependent, N-methyl-d-aspartate (NMDA) glutamate
receptors is diminished. This, in turn, allows greater affinity of the excessive glutamate
to the unobstructed NMDA receptors. This overabundance of NMDA receptor activation
leads to a toxic influx of Ca² into the mitochondria, triggering swelling. This may be a
mechanism for the release of cytochrome c during apoptosis.

								
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