Common Causative Gene Research Articles

Mitochondrial dysfunction and Parkinson’s disease genes: insights from Drosophila

Parkinson's disease (PD), one of the most common neurodegenerative disorders worldwide, currently lacks a cure. Although most PD cases occur sporadically, studies from rare genetic mutations give significant insights into addressing the pathological mechanism of not only familial PD, but also sporadic PD. Recent PD research focuses on generating genetic mutant animal models that recapitulate the features of human PD patients. Significant advances in PD research have resulted from studying Drosophila mutants of several identified PD-associated genes because they show strikingly visible phenotypes. In particular, previous studies with the Drosophila mutants parkin and PINK1, which are two common causative genes among PD familial forms, have suggested strongly that mitochondrial dysfunction is the prominent cause for the PD pathogenesis and that these two PD genes are in a common pathway, with Parkin downstream of PINK1. Recent genetic studies have revealed that the PINK1-Parkin pathway is involved in regulating the mitochondrial remodeling process. In addition, PINK1 was recently found to regulate the localization of Parkin through direct phosphorylation. Here, we briefly review these new and exciting findings in Drosophila PD models and discuss how using these models can further advance PD studies.

Novel PINK1 mutations in early-onset parkinsonism.

PINK1 was recently found to be associated with PARK6 as the causative gene. We performed mutation analysis in eight inbred families whose haplotypes link to the PARK6 region. We identified six pathogenic mutations (R246X, H271Q, E417G, L347P, and Q239X/R492X) in six unrelated families. All sites of mutations were novel, suggesting that PINK1 may be the second most common causative gene next to parkin in parkinsonism with the recessive mode of inheritance.

Genotype-phenotype correlation in CAG-repeat diseases.

The expansion of a CAG repeat is a common causative gene mutation in several hereditary neurodegenerative disorders, including dentatorubral-pallidoluysian atrophy (DRPLA). Although, in DRPLA, it is revealed that the variety of clinical manifestations is related to the variable expansion of the CAG repeat, there are still many problems in the correlation between the symptoms and neuropathologic findings. Recent immunohistochemical studies have revealed that diffuse intranuclear accumulation of mutant proteins with expanded polyglutamine stretches is a significant pathology in DRPLA, and involves a wide range of the CNS regions far beyond the lesion distribution previously established by neuronal loss. This novel pathology may become a clue for elucidating molecular mechanisms of neuronal dysfunction and establishing clinicopathological correlations in CAG-repeat diseases.

Familial Glaucoma Iridogoniodysplasia Maps to a 6p25 Region Implicated in Primary Congenital Glaucoma and Iridogoniodysgenesis Anomaly

Familial glaucoma iridogoniodysplasia (FGI) is a form of open-angle glaucoma in which developmental anomalies of the iris and irido-corneal angle are associated with a juvenile-onset glaucoma transmitted as an autosomal dominant trait. A single large family with this disorder was examined for genetic linkage to microsatellite markers. A peak LOD score of 11.63 at a recombination fraction of 0 was obtained with marker D6S967 mapping to chromosome 6p25. Haplotype analysis places the disease gene in a 6.4-cM interval between the markers D6S1713 and D6S1600. Two novel clinical appearances extend the phenotypic range and provide evidence of variable expressivity. The chromosome 6p25 region is now implicated in FGI, primary congenital glaucoma, and iridogoniodysgenesis anomaly. This may indicate the presence of a common causative gene or, alternatively, a cluster of genes involved in eye development/function.