scholarly journals Mutations in the gene LRRK2 encoding dardarin (PARK8) cause familial Parkinson's disease: clinical, pathological, olfactory and functional imaging and genetic data

Brain ◽  
2005 ◽  
Vol 128 (12) ◽  
pp. 2786-2796 ◽  
Author(s):  
Naheed L. Khan ◽  
Shushant Jain ◽  
John M. Lynch ◽  
Nicola Pavese ◽  
Patrick Abou-Sleiman ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Functional Imaging ◽  
Genetic Data ◽  
Familial Parkinson’S Disease

scholarly journals Identification of TMEM230 mutations in familial Parkinson’s disease (response to comments)

2017 ◽  
Author(s):  
Han-Xiang Deng ◽  
Teepu Siddique
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Clinical Information ◽  
Genetic Data ◽  
Linkage Study ◽  
Sequencing Data ◽  
Disease Response ◽  
Whole Exome Sequencing Data ◽  
Family Based ◽  
Familial Parkinson’S Disease

We recently reported mutations in TMEM230 in familial Parkinson’s disease (PD). Farrer et al raised the concern that mutations in TMEM230 may not be pathogenic to PD. We seriously evaluated Dr. Farrer’s assertions. We obtained updated clinical information and performed several new experiments, including MegaEx chip screening of the family DNA samples with ∼2 million SNPs for whole-genome linkage study and re-analysis of whole-exome sequencing data. We did not find any other locus more robust than the chromosome 20p (TMEM230), nor any other variants with better segregation than TMEM230-R141L to explain the inheritance of PD in the large Mennonite family. Based on the new genetic data from the Mennonite PD family, and the robust genetic data showing additional TMEM230 mutations in multiple PD families, we are confident to conclude that TMEM230 is a new PD-causing gene. Further studies of TMEM230 should provide important mechanistic insights into understanding the vesicle/endosome trafficking/recycling defects in the pathogenesis of PD.

scholarly journals α-Synuclein BAC transgenic mice exhibit RBD-like behaviour and hyposmia: a prodromal Parkinson’s disease model

Brain ◽  
2019 ◽  
Vol 143 (1) ◽  
pp. 249-265 ◽  
Author(s):  
Tomoyuki Taguchi ◽  
Masashi Ikuno ◽  
Mari Hondo ◽  
Laxmi Kumar Parajuli ◽  
Katsutoshi Taguchi ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Transgenic Mice ◽  
Rem Sleep ◽  
Genome Wide Association Study ◽  
Artificial Chromosome ◽  
Genome Wide Association ◽  
Genome Wide ◽  
A Genome ◽  
Familial Parkinson’S Disease

Abstract Parkinson’s disease is one of the most common movement disorders and is characterized by dopaminergic cell loss and the accumulation of pathological α-synuclein, but its precise pathogenetic mechanisms remain elusive. To develop disease-modifying therapies for Parkinson’s disease, an animal model that recapitulates the pathology and symptoms of the disease, especially in the prodromal stage, is indispensable. As subjects with α-synuclein gene (SNCA) multiplication as well as point mutations develop familial Parkinson’s disease and a genome-wide association study in Parkinson’s disease has identified SNCA as a risk gene for Parkinson’s disease, the increased expression of α-synuclein is closely associated with the aetiology of Parkinson’s disease. In this study we generated bacterial artificial chromosome transgenic mice harbouring SNCA and its gene expression regulatory regions in order to maintain the native expression pattern of α-synuclein. Furthermore, to enhance the pathological properties of α-synuclein, we inserted into SNCA an A53T mutation, two single-nucleotide polymorphisms identified in a genome-wide association study in Parkinson’s disease and a Rep1 polymorphism, all of which are causal of familial Parkinson’s disease or increase the risk of sporadic Parkinson’s disease. These A53T SNCA bacterial artificial chromosome transgenic mice showed an expression pattern of human α-synuclein very similar to that of endogenous mouse α-synuclein. They expressed truncated, oligomeric and proteinase K-resistant phosphorylated forms of α-synuclein in the regions that are specifically affected in Parkinson’s disease and/or dementia with Lewy bodies, including the olfactory bulb, cerebral cortex, striatum and substantia nigra. Surprisingly, these mice exhibited rapid eye movement (REM) sleep without atonia, which is a key feature of REM sleep behaviour disorder, at as early as 5 months of age. Consistent with this observation, the REM sleep-regulating neuronal populations in the lower brainstem, including the sublaterodorsal tegmental nucleus, nuclei in the ventromedial medullary reticular formation and the pedunculopontine nuclei, expressed phosphorylated α-synuclein. In addition, they also showed hyposmia at 9 months of age, which is consistent with the significant accumulation of phosphorylated α-synuclein in the olfactory bulb. The dopaminergic neurons in the substantia nigra pars compacta degenerated, and their number was decreased in an age-dependent manner by up to 17.1% at 18 months of age compared to wild-type, although the mice did not show any related locomotor dysfunction. In conclusion, we created a novel mouse model of prodromal Parkinson’s disease that showed RBD-like behaviour and hyposmia without motor symptoms.

scholarly journals CHIP Is Associated with Parkin, a Gene Responsible for Familial Parkinson's Disease, and Enhances Its Ubiquitin Ligase Activity

2002 ◽  
Vol 10 (1) ◽  
pp. 55-67 ◽  
Author(s):  
Yuzuru Imai ◽  
Mariko Soda ◽  
Shigetsugu Hatakeyama ◽  
Takumi Akagi ◽  
Tsutomu Hashikawa ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Ubiquitin Ligase ◽  
Ubiquitin Ligase Activity ◽  
Familial Parkinson’S Disease

scholarly journals Familial Parkinson's Disease Mutant E46K α-Synuclein Localizes to Membranous Structures, Forms Aggregates, and Induces Toxicity in Yeast Models

2011 ◽  
Vol 2011 ◽  
pp. 1-14 ◽  
Author(s):  
Michael Fiske ◽  
Michael White ◽  
Stephanie Valtierra ◽  
Sara Herrera ◽  
Keith Solvang ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Plasma Membrane ◽  
Mutant Form ◽  
Phospholipid Membrane ◽  
Endomembrane System ◽  
Wild Type ◽  
Significant Toxicity ◽  
Familial Parkinson’S Disease

In Parkinson’s disease (PD), midbrain dopaminergic neuronal death is linked to the accumulation of aggregated α-synuclein. The familial PD mutant form of α-synuclein, E46K, has not been thoroughly evaluated yet in an organismal model system. Here, we report that E46K resembled wild-type (WT) α-synuclein in Saccharomyces cerevisiae in that it predominantly localized to the plasma membrane, and it did not induce significant toxicity or accumulation. In contrast, in Schizosaccharomyces pombe, E46K did not associate with the plasma membrane. Instead, in one strain, it extensively aggregated in the cytoplasm and was as toxic as WT. Remarkably, in another strain, E46K extensively associated with the endomembrane system and was more toxic than WT. Our studies recapitulate and extend aggregation and phospholipid membrane association properties of E46K previously observed in vitro and cell culture. Furthermore, it supports the notion that E46K generates toxicity partly due to increased association with endomembrane systems within cells.

Frequency of the ASP620ASN mutation in VPS35 and Arg1205His mutation in EIF4G1 in familial Parkinson's disease from South Italy

2014 ◽  
Vol 35 (10) ◽  
pp. 2422.e1-2422.e2 ◽  
Author(s):  
Monica Gagliardi ◽  
Grazia Annesi ◽  
Patrizia Tarantino ◽  
Giuseppe Nicoletti ◽  
Aldo Quattrone
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
South Italy ◽  
Familial Parkinson’S Disease

scholarly journals A Novel LRRK2 Variant p.G2294R in the WD40 Domain Identified in Familial Parkinson’s Disease Affects LRRK2 Protein Levels

2021 ◽  
Vol 22 (7) ◽  
pp. 3708
Author(s):  
Jun Ogata ◽  
Kentaro Hirao ◽  
Kenya Nishioka ◽  
Arisa Hayashida ◽  
Yuanzhe Li ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Peripheral Blood ◽  
Kinase Activity ◽  
Late Onset ◽  
Causative Gene ◽  
Protein Levels ◽  
Wd40 Domain ◽  
Lrrk2 Protein ◽  
Familial Parkinson’S Disease

Leucine-rich repeat kinase 2 (LRRK2) is a major causative gene of late-onset familial Parkinson’s disease (PD). The suppression of kinase activity is believed to confer neuroprotection, as most pathogenic variants of LRRK2 associated with PD exhibit increased kinase activity. We herein report a novel LRRK2 variant—p.G2294R—located in the WD40 domain, detected through targeted gene-panel screening in a patient with familial PD. The proband showed late-onset Parkinsonism with dysautonomia and a good response to levodopa, without cognitive decline or psychosis. Cultured cell experiments revealed that p.G2294R is highly destabilized at the protein level. The LRRK2 p.G2294R protein expression was upregulated in the patient’s peripheral blood lymphocytes. However, macrophages differentiated from the same peripheral blood showed decreased LRRK2 protein levels. Moreover, our experiment indicated reduced phagocytic activity in the pathogenic yeasts and α-synuclein fibrils. This PD case presents an example wherein the decrease in LRRK2 activity did not act in a neuroprotective manner. Further investigations are needed in order to elucidate the relationship between LRRK2 expression in the central nervous system and the pathogenesis caused by altered LRRK2 activity.

scholarly journals Two large British kindreds with familial Parkinson’s disease: a clinico‐pathological and genetic study

Brain ◽  
2002 ◽  
Vol 125 (1) ◽  
pp. 44-57 ◽  
Author(s):  
D. J. Nicholl ◽  
J. R. Vaughan ◽  
N. L. Khan ◽  
S. L. Ho ◽  
D. E. W. Aldous ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Genetic Study ◽  
Familial Parkinson’S Disease
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