accepted manuscript

ACCEPTED MANUSCRIPT
However, ATP13A2 mutations have also been found in rare cases with juvenile
parkinsonism and only mild additional, atypical features [108].
Familial variants of PD account for up to 10% of PD cases. They usually, but
not exclusively show an early onset of symptoms and are in essence clinically
indistinguishable from sporadic PD [103, 106]. Remarkably, what we know so far
about the function and dysfunction of PD genes confirms the relevance of the
biochemical alterations found in sporadic PD, i.e. mitochondrial dysfunction,
oxidative stress and a dysbalance in protein homeostasis characterized by an increase
in protein misfolding and aggregation accompanied by an impaired removal of
misfolded proteins. Indeed, several PD genes have been associated with
mitochondrial integrity and cellular stress response and quality control systems (rev.
in [109-114]). Thus, insight into the function of PD genes can promote our
understanding of the molecular causes of PD and help to focus research on key
biochemical pathways.
2.1. PINK1
2.1.1. PINK1 and mitochondrial function
ACCEPTED MANUSCRIPT
Mutations in the PINK1 (PTEN-induced putative kinase) gene are the second
most common cause of autosomal recessive, early-onset parkinsonism after parkin
mutations [115]. PINK1 is a 581 amino acid protein with an N-terminal mitochondrial
targeting sequence and a serine/threonine kinase domain (rev. in [116]). Most
pathogenic mutations are missense mutations which cluster to the kinase domain and
have been shown to impair the kinase activity, which is essential for the
neuroprotective activity of PINK1. Increased PINK1 expression confers protection
from apoptotic cell death in various stress paradigms, and loss of PINK1 function
15