0-TESTO COMPLETO.pdf - Fondazione Santa Lucia

Sezione III: Attività per progetti
BACKGROUND
Amyotrophic lateral sclerosis (ALS) arises from the progressive degeneration
of upper motoneurons in the motor cortex, and lower motoneurons in
the brainstem and spinal cord, manifested as progressive muscular weakness,
paralysis and death within 3-5 years. To date, only one drug, riluzole, has been
shown to increase the patients survival, albeit in a very modest way, and none
of the clinical treatment tested so far has shown true efficacy in halting the
course of the disease. A wealth of data pointed out that vulnerability of
motoneurons in ALS likely arises from a combination of several different
mechanisms, including protein misfolding, mitochondrial dysfunction, oxidative
damage, defective axonal transport, excitotoxicity, insufficient growth factor
signaling, and inflammation.
While most of ALS cases are sporadic (sALS), about one fifth of the
cases are familial (fALS). Among fALS cases, approximately 20% are linked
to various dominantly inherited mutations in the gene encoding Cu,Zn
superoxide dismutase (SOD1). The mechanisms through which mutations
in SOD1 lead to late-onset motor neuron degeneration do not implicate a
decrease in the enzyme activity. It is instead assumed that SOD1 mutants
acquire novel neurotoxic properties such as pro-oxidant and pro-apoptotic
activity. The discovery of SOD1 mutations linked with fALS has made possible
the development of an etiological models of the disease. Transgenic mice
expressing human fALS-SOD1 added to their own enzyme have a phenotype
that closely resembles ALS (i.e. adult-onset progressive motor paralysis,
muscle wasting and reduced lifespan). They also express almost all of the
essential histopathological features of the human disease, including the
selective degeneration of motoneurons in the spinal cord, the presence of
ubiquitinated protein aggregates in motor axons and motoneuron perikarya,
in addition to the fragmentation of the Golgi apparatus in motoneurons and
the activation of microglia and astrocytes in the spinal cord and brainstem.
Moreover, several biochemical alterations observed in patients – such as the
appearance of oxidative-stress markers, alterations of mitochondria in
motoneurons and muscle and the activation of phosphorylation cascades –
are, in most cases, preserved in these models [Bendotti, Carrì (2004) Trends
Mol Med 10(8): 393-400; Boillee, Vande Velde, Cleveland (2006) Neuron
52(1): 39-59].
For these reasons, transgenic rodents that express human mutant SOD1
are widely used to screen potential therapeutics for ALS. However, treatments
that interfere with a specific event in the neurotoxic cascade have been
reported to produce a modest increase in lifespan of mice [Carrì, Grignaschi,
Bendotti (2006) Trends in Pharmacol Sci 27(5): 267-273] and up to date no
treatment has been translated effectively from mice to man.
The reasons for such a failure may be diverse. As mentioned above, it has
now been ascertained that ALS is a multifactorial disease and several alterations
have been proposed to contribute to its pathogenesis. Furthermore,
even when caused by a single gene defect, as in the case of mutations in the
enzyme SOD1, ALS is a multisystem disease resulting from a complex cas-
572 2009