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Introduction

Huntingtons disease (HD) is a dangerous neurodegenerative disorder that disrupts


multiple cellular functions and processes including transcription, protein modification, oxidative
stress, and mitochondria function (Bates et al., 2002; Marsh and Thompson, 2004). It is a polyQ
disorder which is caused by an expansion of CAG repeats within a gene. These extra CAG
repeats which encodes the amino acid glutamine (Q), leads to an abnormal protein conformation
and usually protein aggregation. In HD, the CAG repeats occurring alongin the exon 1 of the
Huntingtin genee. (Davies and Rubinsteinz, 2006). The CAG repeats are non-interrupted and
lead to the formation of the Huntingtin protein (Htt) (HDCRG, 1993).

For reasons that are not fully understood, pPoly Q disorders are responsible for the cell
death of neurons leading to several symptoms including chorea, reduced mobility, and eventually
death. Chorea causes, being a disease with involuntary physical movements leading to reduced
mobility. is a major symptom of HD. . 10-25 CAG repeats equate to normal levels of cellular
function. Poly-Q CAG repeats of 36-107 is Huntingtons disease and higher CAG repeat
sequences equate to higher more severe levels of neurodegeneration (Nishimura et al., 2010).

They are caused by the expansion of poly encoding repeats, which are CAG repeats
occurring along exon 1 of the Huntingtin gene. (Davies and Rubinsteinz, 2006). The CAG
repeats are non-interrupted and lead to the formation of the Huntingtin protein (Htt) (HDCRG,
1993). Expansion of poly Q repeats within the Huntingtin protein equate to severity of the
Comment [WU1]: (in tandem) may be better
here than non-interrupted
Comment [WU2]: Not sure I really understand
this statement. The protein is made whether or not
there are repeats.
Comment [WU3]: What type of reference is
this? You need to have references with authors.
Comment [WU4]: Not sure I really understand
this statement. The protein is made whether or not
there are repeats.
Huntingtons disease, which follow accumulation of Huntingtin mutant proteins. (Zhang et al.,
2004).
Chorea, being a disease with involuntary physical movements is a major symptom of
HD. Expansion of poly Q repeats within the Huntingtin protein equate to the severity of the
Huntingtons disease, (Zhang et al., 2004). Psychiatric symptoms and impairment of cognitive
function also have a direct relationship between poly Q expansion and the number of CAG
repeats found (Nishimura et al., 2010), with excess repeats of the CAG sequence leading to
neurodegeneration (Bates et al., 2002). 10-25 CAG repeats equate to normal levels of cellular
function. Poly-Q CAG repeats of 36-107 is Huntingtons disease and higher CAG repeat
sequences equate to higher more severe levels of neurodegeneration (Nishimura et al., 2010).
Although several studies indicate that poly Q dependent aggregation is a leading cause of
neurodegeneration in Huntingtons disease, others suggest aggregation is a neuroprotective
mechanism. (Saudu,1998; Arrasate, 2004). Aggregation inhibitors have beneficial effects in
Drosophila and mouse models of Huntingtons Disease (Zhang et al., 2004).
Model organisms such as Drosophila have been utilized to gain a better understanding of
the cause of HD and to test potential therapeutic agents for HD. models Due to Drosophilas?
(see comment) have beneficial characteristics including late onset, reduced longevity, and the
ability to produce large progeny. (Bonni et al., 2003; Marsh et al., 2003; Marsh and Thompson,
2004). In our HD Drosophila models there will be three poly Q groups (polyQ-22, polyQ-48,
and polyQ-108). Poly-Q 22 will be the control for the experiment, meaning 22 CAG repeats with
normal function. Poly-Q 108 the extreme severe group of the three, meaning very poor
performance and cognitive ability within the HD Drosophila. Chemical C2-8 has been identified
Comment [WU5]: The period should go after
the citation.
Comment [WU6]: This statement is not enough.
This idea should be an entire paragraph of what are
some of the hypotheses on how aggregation can
lead to neurodegeneration.
Comment [WU7]: This doesnt seem to go
together. Think about exactly what you want to say
here and then it will be easier to rearrange to figure
out what needs to go to this paragraph.
Comment [WU8]: You sort of jump into this
statement. Lets first state that model organisms
have been utilized to understand more about the
disease. I think this should go a couple of
paragraphs down.
Comment [WU9]: Decide what your
abbreviation for these lines will be and make sure it
is consistent throughout the paper.
to directly target poly Q aggregation (Zhang et al., 2004), which we are hoping will be a
potential therapeutic agent.
Compounds that have inhibited aggregation of the huntinton protein have alleviated
severe HD symptoms in Drosophila and mouse models of Huntingtons Disease (Zhang et al.,
2004). Several identified small molecules halt the development of poly Q aggregates by targeting
cellular pathways (Zhang et al., 2004). Compound C28 potently inhibits polyQ aggregation
(Zhang et al., 2004). When Drosophila was fed food containing C2-8, significant relief in 200
M dose amounts were shown within the first 8 hours with documentation of percentage rescue
of around 40%. (Zhang et al., 2004). C28 blocks the polymerization step of the process, but
only at very high concentrations. Thus C2-8 may be a This information serves as a good
indicator of a potential therapeutic agent for Huntingtons disease. However, this compound has
not been tested to see if mobility or lethality was reduced. the poly Q disorders testing mobility
and lethality.
Our Since C2-8 compound was able to reduce the aggregation of Huntintin protein, my
question is to determine if the C2-8 compound, when fed to HD induced Drosophila will
increase lifespan and mobility. We want to see if there is a relationship between the amount of
C2-8 and the lethality. If C2-8 does target poly-Q aggregation, will it also improve performance
and help flies live longer in HD induced Drosophila models? I will test two concentration of
C2-8 to determine if it will improve mobility and increase lifespan. We want toThen, I will
compare the difference of HD Drosophila fed on each concentration of C2-8 to HD Drosophila
and not fed on C2-8. compare them to non-treated groups.
I hypothesize compound C2-8 will reduce lethality and show increase in performance
values when compared to non-treated HD groups due to potent poly Q aggregation inhibition. I
Comment [WU10]: Not sure what you mean
here. Aggregation does not depend on cell signaling
pathways. What did they actually say in this paper.
Comment [WU11]: Not correct word here use
more scientific terminology. Describe the results of
the experiment.
Comment [WU12]: What type of rescue and
how is this different from what you are doing? You
have to make sure that the reader understands
what has been done and what still needs to be
done.
Formatted: Font: Italic
Comment [WU13]: This is where you should
place the info about the strains.
will see a relationship of improved performance when I feed HD Drosophila with compound C2-
8.
I predict if I feed poly Q-22, poly Q-48, and poly-Q 108 HD Drosophila groups over a 2
month period with 10 M and 200 M concentrations of C2-8, then treated groups will climb
higher in climbing assays improve mobility when compared to non-treated groups. Treated
groups are also predicted to live significantly longer when compared to non-treated groups,
decreasing the lethality of HD.


















Literature Cited
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Nishimura, Y., Yalgin, C., Akimoto, S., Doumanis, J., Sasajima, R., Nukina, N., Miyakawa,
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Saudou, F., Finkbeiner, S., Devys, D.&Greenberg, M. E. (1998) Huntingtin acts in the nucleus
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The Huntington s Disease Collaborative Research Group.(1993). A novel gene containing a
trinucleotide repeat that is expanded and unstable on Huntington s disease
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Wyttenbach, A., Arrigo, A.P. (2000). The Role of Heat Shock Proteins during
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Zhang, X., Smith, D., Merlin, B., Engemann, S., Russel, D., Roark, M., Washington, S.
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