0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
BACKGROUND
Huntington’s disease (HD) is an autosomal-dominant inherited neurodegenerative
disorder characterized by motor dysfunction, cognitive decline and
emotional and psychiatric disturbance [Wilson et al. 1987]. The genetic mutation
involves the IT15 gene (The Huntington’s Disease Collaborative Research
Group (1993) and is characterized by a CAG expansion beyond the normal 10-
35 repeat range, resulting in formation of a mutant huntingtin protein with an
expanded poly-glutamine repeat region [Albin, Tagle 1995]. Although mutant
huntingtin is expressed throughout the brain, the medium spiny neurons of
the striatum are particularly vulnerable to the toxicity of this protein. Indeed,
striatal pathology is believed to underlie the motor symptoms that are diagnostic
for the disease. However, it is also becoming increasingly clear that
there is significant cortical pathology in HD. This may stem indirectly from
the striatal damage or as a direct result of an effect of mutant huntingtin on
cortical neurons. Thus, there is intense interest in therapies that may reduce
the dysfunction and loss of striatal and cortical neurons in HD.
The cause of striatal and cortical neuron loss in HD is under intense
investigation. There is evidence to suggest that mutant huntingtin interacts
with and impairs the function of a number of transcription factors [Sugars,
Rubinsztein 2003], in particular the cAMP response element-binding protein
(CREB) [Steffan et al. 2001; Sugars, Rubinsztein 2003; Sugars et al. 2004].
CREB-mediated transcription is required for the survival of adult CNS neurons
[Hardingham et al. 2001; Mantamadiotis et al. 2002] and induction of
CREB signaling has a protective role in several animal models of neurodegeneration
[Walton et al. 1996; Walton et al. 1999; Mantamadiotis et al. 2002].
Inhibition of CREB-mediated gene transcription has been hypothesized to
contribute to neuronal loss in HD [Kazantsev et al. 1999; Steffan et al. 2000;
Nucifora et al. 2001; Steffan et al. 2001; Jiang et al. 2003] and a decreased
transcription of CREB-regulated genes was observed in HD transgenic animals
[Luthi-Carter et al. 2000; Nucifora et al. 2001; Wyttenbach et al. 2001].
Therefore, drugs targeted at counteracting CREB loss of function may be considered
as powerful tools to treat HD.
The above hypothesis was first directly interrogated in our studies utilizing
the cyclic nucleotide phosphodiesterase type IV (PDE4) inhibitor,
rolipram. PDE4 [Houslay, Adams 2003] is one of the eleven families of phosphodiesterases
that regulate through metabolic inactivation cyclic nucleotide
signaling throughout the body [Conti, Beavo 2007], including in brain [Menniti
et al. 2006]. PDE4 inhibition results in activation of cAMP signaling pathways
and, consequently, increased CREB phosphorylation and activation
[Hosoi et al. 2003; Jacob et al. 2004; Lee et al. 2004]. We have shown that
rolipram reduces striatal degeneration in our rat quinolinic acid (QA) model
of HD pathology [DeMarch et al. 2007] as well as in a transgenic model of
HD, the R6/2 mice [DeMarch et al. 2008]. These beneficial effects are hypothesized
to result from the increased CREB phosphorylation, and expression of
the downstream neurotrophic factor BDNF, that occurred with rolipram treatment
in both disease models.
666 2009