A role of mitochondrial complex II defects in genetic models of Huntington’s disease expressing N-terminal fragments of mutant huntingtin.

Huntington’s disease (HD) is a neurodegenerative disorder caused by an abnormal expansion
of a CAG repeat encoding a polyglutamine tract in the huntingtin protein (Htt). The mutation
leads to neuronal death through mechanisms which are still unknown. One hypothesis is that
mitochondrial defects may play a key role. In support of this, the activity of mitochondrial
complex II (C-II) is preferentially reduced in the striatum of HD patients. Here, we studied CII expression in different genetic models of HD expressing N-terminal fragments of mutant
Htt (mHtt). Western blot analysis showed that the expression of the 30 kDa Iron-Sulfur (Ip)
subunit of C-II was significantly reduced in the striatum of the R6/1 transgenic mice while the
levels of the FAD containing catalytic 70 kDa subunit (Fp) were not significantly changed.
Blue native gel analysis showed that assembly of C-II in mitochondria was altered early in
N171-82Q transgenic mice. Early loco-regional reduction of C-II activity and Ip protein
expression was also demonstrated in a rat model of HD using intrastriatal injection of
lentiviral vectors encoding mHtt. Infection of the rat striatum with a lentiviral vector coding
the C-II Ip or Fp subunits induced a significant overexpression of these proteins that led to
significant neuroprotection of striatal neurons against mHtt neurotoxicity. These results
obtained in vivo support the hypothesis that structural and functional alterations of C-II
induced by mHtt may play a critical role in degeneration of striatal neurons in HD, and that
mitochondrial targeted therapies may be useful in its treatment.



Source:  Human Molecular Genetics

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