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

Etiology and pathogenesis of PD
INTRODUCTION
The cause of most cases of PD remains unclear. By the date several pathogenic
mechanisms based on environmental, genetic and histopathological findings have been
implicated in this disease. They may be primary activating events for the disease and
secondary events involved in promoting progression of PD over time. The contributions
of genetic and environmental risk factors and the impact of compensatory mechanisms
on PD progression are still unanswered questions. Some forms of PD have been
associated to specific environmental causes (Langston et al. 1983, Thrash et al. 2007,
Jang et al. 2008), while a few familial forms of PD and related parkinsonism are related
to apparent genetic causes (Biskup et al. 2008, Gasser 2009).
Genetics of PD
In the majority of PD cases, there is no apparent genetic linkage and the disease
is referred to as “sporadic” or idiopathic PD. Thus, familial cases only represent a 5-
10% of the whole affected population. The disease is inherited and defined by at least
one relative (parent or sibling) also having PD. It is not always clear if this is due to
heritable genetic factors or shared environment. But an inherited genetic contribution
was put forward by various studies, mono- and dizygotic twins and families with PD
history (Tanner 1999, Thacker and Ascherio 2008).
An increasing number of single gene mutations causing familial PD have been
identified (Table 4). They show both autosomal dominant and recessive as well as X-
linked modes of inheritance (Vila and Przedborski 2004, Wood-Kaczmar et al. 2006).
Many of these have also been found in apparently sporadic cases (Warner and Schapira
2003) suggesting that they may act as susceptibility factors. Chromosomal regions have
been designated as “PARK” genes. These include two autosomal dominant genes: �-
synuclein (SNCA) (Polymeropoulos et al. 1997, Krüger et al. 1998) and leucine-rich
repeat kinase 2 LRRK2 (Paisán-Ruiz et al. 2004, Zimprich et al. 2004), and three
autosomal recessive genes: parkin (PRKN) (Kitada et al. 1998), PTEN-induced putative
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