Mechanisms of aluminium neurotoxicity in oxidative stress-induced ...

Misfolding and aggregation of proteins
INTRODUCTION
Dysfunction at any stages of protein production (transcription and translation,
post-translational modification, trafficking and degradation) can lead to malformed
proteins and aggregation. There is now compelling evidence that protein aggregation
and abnormal processing of proteins are involved in the pathogenesis of PD (Schulz and
Dichgans 1999). Despite the rarity of the familial forms of PD, the identification of
single genes linked to this disease has provided decisive insights into probable
mechanisms of its pathogenesis. Mutations in the genes α-synuclein, parkin or UCH-L1
are thought to impair the protein degradation pathway involving ubiquitination and the
proteasome (Figure 18B).
The protein α-synuclein is the major constituent of the LB. In its native state,
monomeric α-synuclein is a soluble unfolded protein that under certain conditions is
prone to misfold and to aggregate forming oligomeric species. These oligomers, termed
protofibrils, are soluble and can then become amyloid-like fibrils which are insoluble.
These latter are the major components of LB (Spillantini et al. 1998) and can also form
LN in neuronal processes. Mutations on SNCA, the gene encoding α-synuclein, cause a
rare autosomant dominant form of familial PD (Polymeropoulos et al. 1997, Kruger et
al. 1998). Genomic rearrangement in the form of duplication and triplication of the wild
type (wt) SNCA gene cause typical and atypical PD, respectively (Singletton et al.
2003, Chartier-Halin et al. 2004, Ibañez et al. 2004, Fuchs et al. 2007) and the presence
of increased copy numbers of the wt α-synuclein gene causes PD (Ibañez et al. 2004).
Moreover, α-synuclein aggregates are also found in various other neurodegenerative
diseases termed synucleinopathies, such as MSA, DLB, and pure autonomic failure
(Trojanowski and Lee 2002).
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