| The hereditary spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative disorders characterized by slowly progressive in coordination of gait and often associated with poor coordination of hands, speech, and eye movements, most of them are inherited in an autosomal dominant manner, and lead to the early death and disability of patients involved. To date, at least 30 genes responsible for SCAs have been cloned or located to their distinct regions on certain chromosome but still waited to be cloned. Spinocerebellar ataxia type 3, also known as Machado Joseph disease (SCA3/MJD), is the most common genotype of SCAs in world wide and account almost for 50% in Chinese SCAs patients. Besides SCA3/MJD, at least 9 human neurodegenerative diseases known as polyQ diseases show considerable similarity in pathology, pathgenesis, and clinical manifestations because they share a common molecular mechanism involving expansion of a polyglutamine tract (polyQ) within their respective disease-causing proteins, and expanded polyQ confers a toxic gain-of-function property on the otherwise unrelated disease proteins, leading to neuronal dysfunctions, cell loss and the form of Neuronal intranuclear inclusions in specific areas (spinal cord, cerebella, brain stem, et al. ). In SCA3/MJD, the glutamine repeat, which is located near the carboxyl terminus of the protein, normally contains 12-40 repeats and becomes expanded to 55-84 repeats pathologically. The longer the repeat, the earlier the onset and the more severe the disease.The mechanism of SCA3/MJD is still not fully understood, as were known. In particular, abnormal protein conformation(s) promoted by polyQ expansion seems to be the key to pathogenesis in SCA3/MJD and other polyQ diseases. This toxicity is linked to protein misfolding and oligomerization of the mutant protein alters interactions of the mutant protein with its normal interacting partners, leads to dysfunction of proteins, and interferes with the basic cell process such as gene transcription, degrade of protein, oxidative stress and survival/apoptotic pathway. Moreover, expanded polyglutamine proteins form aggregates, including neuronal intranuclear inclusions (NIIs), a common pathologic hallmarker of disease, possibly due to misfolding of proteins. Histology and Immunocytochemistry studies show the neuronal intranuclear inclusions (NIIs) often contain other misfolding proteins, components of the proteasome system, and molecular chaperones. The presence of chaperones in NIIs raises the possibility that chaperones may contribute to pathology in situations. It is suggested that disease pathogenesis may include activation of cellular stress pathways to help refold, disaggregate or degrade the mutant disease proteins. Some studies indicated that over expression of specific chaperone proteins Hsp70 and Hsp40 suppressed neurodegeneration induced by polyQ in transfected cells and Drosophila models. As one of chaperone proteins, small molecular heat shock protein Hsp22 plays important roles in maintaining cellular functions during aging, promoting protein renaturation through protein folding, and inhibiting cytochrome C-mediated activation of casepases and protect cell against apoptosis. Because oxidative damage is often observed in polyQ disease and mitochondria are sensitive to reactive oxygen species, Hsp22 is a protein localized in mitochondria, the increased level of Hsp22 could protect mitochondria protein. In our previous work, the mutation of Hsp22 gene causes Charcot-Marie-Tooth disease, another kind of neurodegenerative disease. It is also suggested that Hsp22 may contribute to the normal structure and function of protein. Therefore, we have enough reason to make a hypothesis that over-expression of Hsp22 may reduce polyQ toxicity, and suppress neurodegeneration caused by the mutant ataxin-3.As a classic animal model, transgenic drosophila play an important role in research of neurodegenerative and neurogenetic disorders. To date, many transgenic drosophila models were set up for neurodegenerative and neurogenetic disorders including SCA3/MJD.We expressed a truncated version of the human expanded ataxin-3 protein (MJDtr-Q78) in both the neural system and eyes using the GAL4-UAS transformation system. This system allows targeted gene expression when transgenic flies bearing a UAS transgene are crossed with fly lines that express GAL4 in tissue-specific patterns. We used the gene promoter gmr-GAL4 and elav-GAL4, which drive expression in all cells of the developing eye and neuron, respectively. Expression of MJDtr-Q78 had severe effects on morphology and pigmentation of the eye, led to the death of all Drosophila lavas for defected development and neuronal intranuclear inclusions (NIIs) formation. Then, we over expressed the Hsp22 in flies, and found that over expression of endogen Drosophila Hsp22 can notably suppress the toxicity of MJDtr-Q78, and the level of Hsp22 expression was in consistent with rehabilitation for degeneratives of drosophila eyes, drosophila lifespan and the number of nuclear inclusion. It is confirmed that expression of Hsp22 protects the SCA3/MJD from neurodegeneration on model animal.These studies indicate that manipulating specific molecular chaperones including Hsp22 may provide a means of treating neurodegenerative diseases including polyQ disease associated with abnormal protein conformation and toxicity. In these ways, the transgenic drosophila models could help us to further understand the pathogenesis of neurodegenerative diseases including polyQ disease.
|
PDF Full Text Request