Abstract
Alexander’s disease (AxD) is a rare, usually relentlessly progressive disorder of astroglial cells in the central nervous system related to mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP). The pathophysiology of AxD is only partially understood. Available data indicate that an excessive GFAP gene expression may play a role. In particular, a “threshold hypothesis” has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP should be sufficient to cause disease. Thus, strategies based on reducing cellular mutant GFAP protein levels and/or activating biological processes involved in the correct protein folding could be effective in counteracting the toxic effect of misfolded GFAP. Considering that clomipramine (CLM), which has been selected by a wide small molecules screening as the greatest inhibitory potential drug against GFAP expression, is contraindicated because of its proconvulsant activity in the infantile form of AxD, which is also characterized by the occurrence of epileptic seizures, two powerful antiepileptic agents, carbamazepine (CBZ) and phenytoin (PHT), which share specific stereochemical features in common with CLM, were taken into consideration in a reliable in vitro model of AxD. In the present work, we document for the first time that CBZ and PHT have a definite inhibitory effect on pathological GFAP cellular expression and folding. Moreover, we confirm previous results of a similar beneficial effect of CLM. In addition, we have demonstrated that CBZ and CLM play a refolding effect on mutant GFAP proteins, likely ascribed at the induction of CRYAB expression, resulting in the decrease of mutant GFAP aggregates formation. As CBZ and PHT are currently approved for use in humans, their documented effects on pathological GFAP cellular expression and folding may indicate a potential therapeutic role as disease-modifying agents of these drugs in the clinical management of AxD, particularly in AxD patients with focal epilepsy with and without secondary generalization.
Highlights
Alexander’s disease (AxD, MIM#203450) is a rare, usually relentlessly progressive genetic disorder of astroglial cells in the central nervous system related to heterozygous mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP) (Brenner et al, 2001)
As GFAP overexpression is considered a main pathogenetic determinant in AxD leading to GFAP accumulation, and the small heat shock proteins overexpression a potential endogenous tool to counteract GFAP misfolding and cellular protein accumulation, the expression of GFAP and alphaBCrystallin has been investigated in U251-MG cells after 24 and 48 h treatments
We have observed that 24 h treatment with CLM was able to downregulate GFAP and to upregulate alphaB-crystallin expression, suggesting that this drug may have a beneficial effect by activating at least two definite metabolic pathways involved in mutant GFAP accumulation (Figure 1B)
Summary
Alexander’s disease (AxD, MIM#203450) is a rare, usually relentlessly progressive genetic disorder of astroglial cells in the central nervous system related to heterozygous mutations in the gene encoding the type III intermediate filament protein, glial fibrillary acidic protein (GFAP) (Brenner et al, 2001). Compared to the infantile form, AxD type II has a slower progression and cognitive impairment is usually absent (Balbi et al, 2010; Prust et al, 2011). A “threshold hypothesis” has been reported, suggesting that mutant GFAP representing about 20% of the total cellular GFAP is sufficient to cause disease (Hagemann et al, 2005). Molecular mechanisms regulating brain GFAP levels could represent molecular targets, too (Cho et al, 2010)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
