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Home  > Department of Neuropathology  > Research Activities  > A common mechanism underlying two polyglutamine diseases (~2011)

A common mechanism underlying two polyglutamine diseases (~2011)

Fig 1 Supplementation of HMGB proteins rescue eye degeneration by mutant ataxin-1 protein.

Although an intriguing feature of neurodegenerative disorders is that specific types of neurons undergo degeneration (selective neuronal death), it is also accepted that expansion of polyglutamine tract in multiple proteins commonly leads to production of structurally abnormal proteins and causes neurodegeneration. This concept that mutant proteins with abnormal structures induce neurodegeneration can also be extended to Alzheimer's disease, Parkinson's disease and other neurodegenerative diseases. However, the reason why these structurally abnormal proteins commonly cause cellular dysfunction and death remains unknown.
Recent data from our laboratory and the other laboratories suggest that inclusion body (huge aggregates of mutant proteins within the cell) by itself is protective rather than toxic to neurons (Tagawa et al., J Neurochem 2004; Arrasate et al., Nature 2004). Therefore, the toxicity of mutant protein should not be derived from aggregation or should not come from sequestration of normal proteins into the inclusion body. Instead, it would be certain effects of soluble forms of mutant proteins on physiological proteins.
We therefore asked which kinds of physiological protein are affected in neurons expressing mutant polyglutamine proteins. Especially, we are interested in soluble nuclear proteins because several reports definitely showed that nuclear translocation of mutant proteins is indispensable for pathogenesis. Firstly, we asked quantitative changes of physiological proteins in the soluble nuclear proteins by using proteomics analysis. In this analysis, we used two disease proteins (ataxin-1 and huntingtin) and three types of neurons (cortical, striatal and cerebellar neurons). We evaluated quantitative changes of spots on 2-dimensional gels, and in parallel identified proteins corresponding to the spots. Through these analyses, we found that both of the mutant polyglutamine proteins reduced HMGB proteins in vulnerable neurons whereas we did not change HMGB remarkably in resistant proteins.
HMGB proteins change conformation of genome DNA and play critical roles in transcription, DNA repair and other nuclear function. We found that these nuclear functions are impaired in neurons with a low level of HMGB proteins and that supplementation of HMGB proteins recovers the impairment. This rescue effect was also found in Drosohila model in vivo (Figure 1). We also found that mutant polyglutamine proteins bind to HMGB protein and accelerates their degradation. Collectively, mutant polyglutamine proteins, at least of two polyglutamine diseases proteins, commonly impair nuclear function of neurons via reduction of HMGB proteins.

Fig 2 Relationship between early aging and neurodegenerative disorders. Early aging disorders are caused by mutation of DNA repair genes. In polyglutamine diseases, the mutant proteins are detoxified in youth by proteasome or autophagy systems. When the patients become middle age, mutant proteins above a threshold impair DNA repair functions. After the onset, the pathologies might be homologous.

In addition to identification of a novel and common pathological player in the polyglutamine diseases, this study showed that DNA damage is a common pathology in polyglutamine diseases. This concept is brand new for polyglutamine diseases, and could be a target to develop new types of therapeutics. Furthermore, this finding unraveled a critical similarity between aging and neurodegeneration. Many hereditary aging disorders including Cockayne syndrome, Werner syndrome, Xeroderma Pigmentosa (XP) and Niemegen syndrome are caused by mutation of DNA repair proteins. Also several hereditary neurodegenerative diseases such as ataxia-telangiectasia, SCAN1, and EAOH are caused by mutation of DNA repair genes. Therefore, our data cast another light on the molecular similarity between aging and neurodegeneration. In this specific case, although mutant proteins are not DNA repair proteins by themselves, when their amounts become higher than a certain level, they impair DNA repair functions through interaction with HMGB proteins, and they cause "aging of neurons" in a homologous manner to early aging disorders (Figure 2).