First, although some of the Mendelian forms of PD are very rare (including those caused by alfa-synuclein, DJ-1, and PINK1 mutations) they are facilitating greatly the dissection of the molecular pathways that lead to death of dopaminergic neurons; these pathways might also be implicated in the pathogenesis of the common forms of PD.
However, in a large Saudi family with PD with at least 3 consanguineous marriages between first cousins, we detected a threonine to methionine substitution at codon 313 (T313M) PINK1 mutation that affected the kinase domain.
This study reports the first case of autosomal recessive PD with digenic inheritance and demonstrates that DJ-1 and PINK1 physically associate and collaborate to protect cells against stress via complex formation.
To determine the prevalence of PINK1 mutation in Taiwanese population, we conducted genetic analysis of PINK1 mutation in 73 early onset sporadic PD and 94 normal control subjects.
Fractionation studies of lysates showed that PINK1 cleavage was enhanced by proteasomal stress in vitro and correlated with increased expression of the processed PINK1 protein in PD brain.
In the available patients with parkin, PINK1, SCA2 and SCA3, the dopamine transporter (DAT) scan revealed that the reduction of uptake was primarily observed in the bilateral putamen, basically sharing a similar pattern with that in idiopathic Parkinson's disease.
We screened for parkin and PINK1 mutations in a panel of 177 autosomal recessive Parkinson's disease families with ages at onset < or =60 years, mostly from Europe.
These studies provide for the first time in vivo morphological and biochemical evidence to support a mitochondrial localization of PINK1 and underpin the significance of mitochondrial dysfunction in the pathogenesis of nigral cell degeneration in Parkinson's disease.
The autosomal recessive pattern of inheritance of PINK1 mutations suggests that PINK1 is neuroprotective and therefore loss of PINK1 function causes PD.
Recently, multiple genes mediating familial forms of Parkinson's disease have been identified, including PTEN-induced kinase 1 (PINK1; PARK6) and parkin (PARK2), which are also associated with sporadic forms of Parkinson's disease.
To date 11 forms of familial Parkinson's disease (PD) have been mapped to different chromosome loci, of which 6 genes have been identified as the causative genes, i.e., alpha-synuclein (SNCA), parkin, UCH-L1, PINK1, DJ-1, and LRRK2.