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1/29/15
Progress Towards Finding Cure for HSP
interfered with so that it will not synthesize that protein as much. In this specific case, Orso et al.
interfere with the RNA in relation to Dspastin so that the Dspastin is not synthesized as much.
This is exactly why it is called a knockdown of Dspastin: because it eliminates Dspastin
synthesis. After knocking down the Dspastin, they observed the flight of the Drosophila flies and
saw how their motor control was affected. More specifically, the flies climb up speed and
success was adversely affected by the Dspastin knockdown. Lastly, they used fluorescence
microscopy to verify neuronal damage. Essentially, they used a fluorescent microscope and
inspected an antibody that appears in stable microtubules and would light up when fluorescent
light hits it. What they found was that regions that were lighting up before were no longer
lighting up because they were no longer made up of stable microtubules but rather destabilized
microtubules. The second thing Orso et Al. did was they over expressed Dspastin. What this
means is that they over emphasized the gene so that Dspastin was synthesized even more. Again,
they analyzed how the flies motor control was affected and used fluorescence microscopy to
examine neuronal damage. Lastly, Orso et Al. injected the flies with vinblastine and analyzed
whether that would help the flies by observing their motor control again. They did this because
of Jordan and Wilsons work that indicated that Vinca Alkaloids could be used to treat
microtubule disorders.
Orso et al. concluded that Dspastin mutations empirically correlate with and play a
prominent role in the development of HSP. Firstly, Orso et Al. found that a knockdown of
Dspastin lead to phenotypes very similar to Hereditary Spastic Paraplegias. What this means is
that they found that a lack of Dspastin lead to the symptoms of HSP to appear. More specifically,
it was more difficult for the flies to climb up. The same results were found for the overexpression
of Dspastin. That is, the flies microtubules had rigidified. This specific result was found from
the fluorescent microscopy in which the parts that should have had functioning microtubules
were not lighting up because they were not functioning as well as they were supposed to be
functioning. Now, when Orso et Al. injected the vinblastine into the flies, the flies symptoms
began to subside because the vinblastine de-ossified the microtubules. What this means is that
the thing HSP was targeting and making very rigid and stagnant was made more flexible by the
vinblastine and therefore the effect of the HSP was treated by the Vinblastine in the Drosophila
flies. Also, the parts affected by the HSP that were made not visible to the fluorescent
microscope were made visible again once the Vinblastine was administered to the flies.
Because of Orso et al.s work, major breakthroughs in treating Hereditary Spastic
Paraplegias can be made such as developing a comprehensive treatment that mitigates the effects
of HSP like difficulty of walking or stiffness of the legs. Earlier on, two scientists, Jordan and
Wilson, demonstrated that anti-cancer drugs that targeted microtubules like Vinca Alkaloids
could suppress microtubule ossification without decreasing microtubule mass. Using this
information, Orso et al. experimented with Vinblastine (a Vinca Alkaloid) to check whether it
could be used as a treatment for Hereditary Spastic Paraplegias. Orso et al. have now
demonstrated that Vinblastine can be used to treat HSP-like diseases in flies because it stabilizes
the ossified microtubules by making them more flexible again and therefore mitigates many of
the effects of HSP in flies. This sets up a framework for how other scientists can proceed in
treating HSP because they now know to look for treatments that accomplish a similar thing in the
context of microtubules. Not only have Orso et al. tested a treatment on flies, but they have
made a major breakthrough on what causes HSP and even the dynamics on how it causes the
symptoms of HSP. This means treatments can be developed on multiple levels, or at least
research on multiple levels can be made to get closer to finding the cure to Hereditary Spastic
Paraplegias.
Bibliography
1. Jordan, Mary Ann, and Leslie Wilson. Microtubules as a Target for Anticancer Drugs. Nature
Reviews Cancer 4.4 (2004): 253-65. Web.
2. Orso, G. Disease Related Phenotypes in a Drosophila Model of Hereditary Spastic Paraplegia
Are Ameliorated by Treatment with Vinblastine. Journal of Clinical Investigation 115.11 (2005):
3026-034. Web.