Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1

  title={Hereditary Early-Onset Parkinson's Disease Caused by Mutations in PINK1},
  author={Enza Maria Valente and Patrick M. Abou-Sleiman and Viviana Caputo and Miratul M. K. Muqit and Kirsten Harvey and Suzana Gispert and Zeeshan Ali and Domenico Del Turco and Anna Rita Bentivoglio and Daniel G. Healy and Alberto Albanese and Robert Luke Nussbaum and Rafael González-Maldonado and Thomas Deller and Sergio Salvi and Pietro Cortelli and William P. Gilks and D. S. Latchman and Robert J. Harvey and Bruno Dallapiccola and Georg Auburger and Nicholas W. Wood},
  pages={1158 - 1160}
Parkinson's disease (PD) is a neurodegenerative disorder characterized by degeneration of dopaminergic neurons in the substantia nigra. We previously mapped a locus for a rare familial form of PD to chromosome 1p36 (PARK6). Here we show that mutations in PINK1 (PTEN-induced kinase 1) are associated with PARK6. We have identified two homozygous mutations affecting the PINK1 kinase domain in three consanguineous PARK6 families: a truncating nonsense mutation and a missense mutation at a highly… 
Mutational analysis of the PINK1 gene in early-onset parkinsonism in Europe and North Africa.
It is suggested that PINK1 is the second most frequent causative gene in early-onset Parkinson's disease with a slowly progressive phenotype, indistinguishable from early-ONSet patients with parkin mutations.
Genes associated with Parkinson syndrome
The monogenic variants are important tools in identifying cellular pathways that also shed light on the molecular pathogenesis of sporadic PS and some of these genes may play a role in the etiology of the common sporadic form of PS.
Recessive Parkinson's disease
Recent advances in knowledge about genes associated with recessive PD, including parkin, PINK1, and DJ‐1 are reviewed, suggesting that these gene products share a common pathway to nigral degeneration in both familial and sporadic PD.
New aspects of genetic contributions to Parkinson’s disease
Three genes have been identified to cause autosomal-recessive early-onset parkinsonism: parkin, DJ1, and PINK1, which are thought to be involved in the proteasomal protein degradation pathway, in the cell’s response to oxidative stress, and in mitochondrial function.
Update on the genetics of Parkinson's disease
  • T. Gasser
  • Biology
    Movement disorders : official journal of the Movement Disorder Society
  • 2007
Evidence is emerging that at least some of these genes may play a direct role in the etiology of the common sporadic form of Parkinson's disease, and the cellular pathways identified in rare monogenic variants of the disease also shed light on the molecular pathogenesis in typical sporadic PD.
Analysis of the PINK1 gene in a large cohort of cases with Parkinson disease.
Autosomal recessive mutations in PINK1 are a rare cause of young-onset Parkinson disease, including the first reported compound heterozygous mutation (Glu240Lys and Leu489Pro) and a homozygous Leu347Pro mutation in 2 unrelated young-ONSET Parkinson disease patients.
Genetics of familial Parkinson's disease
The identification of mutations in a-synuclein (SNCA), parkin (PARK2), ubiquitin C-terminal hydrolase L1 (UCHL1), PTEN-induced kinase 1 (PINK1), DJ-1, nuclear receptorrelated 1 (Nurr1) and leucine-rich repeat kinase 2 (LRRK2) genes has confirmed the role of genetics in familial forms of PD.
Pathogenesis of familial Parkinson’s disease: new insights based on monogenic forms of Parkinson’s disease
Recent progress in knowledge about the genes associated with familial PD is reviewed, revealing that PD‐associated genes play important roles in cellular functions, such as mitochondrial functions, ubiquitin‐proteasomal system, autophagy‐lysosomal pathway and membrane trafficking.


Localization of a novel locus for autosomal recessive early-onset parkinsonism, PARK6, on human chromosome 1p35-p36.
A large Sicilian family with four definitely affected members (the Marsala kindred) was identified, characterized by early-onset parkinsonism, with slow progression and sustained response to levodopa, and the Parkin-associated phenotype is broad, and some cases are indistinguishable from idiopathic PD.
Molecular Pathways of Neurodegeneration in Parkinson's Disease
Strategies aimed at restoring complex I activity, reducing oxidative stress and α-synuclein aggregation, and enhancing protein degradation may hold particular promise as powerful neuroprotective agents in the treatment of PD.
Park6‐linked parkinsonism occurs in several european families
Features typical of autosomal recessive juvenile parkinsonism, including dystonia at onset and sleep benefit, were not observed in PARK6‐linked families, thus making the clinical presentation of late‐onset cases indistinguishable from idiopathic Parkinson's disease.
Chronic systemic pesticide exposure reproduces features of Parkinson's disease
It is reported that chronic, systemic inhibition of complex I by the lipophilic pesticide, rotenone, causes highly selective nigrostriatal dopaminergic degeneration that is associated behaviorally with hypokinesia and rigidity.
Understanding cell death in parkinson's disease
Evidence enables us to hypothesize that a failure to process structurally modified proteins in regions of the brain exhibiting oxidative stress is a cause of both familial and sporadic PD.
α-Synuclein is phosphorylated in synucleinopathy lesions
It is shown by mass spectrometry analysis and studies with an antibody that specifically recognizes phospho-Ser 129 of α-synuclein, that this residue is selectively and extensively phosphorylated in synucleinopathy lesions and promoted fibril formation in vitro.
An In Vitro Model of Parkinson's Disease: Linking Mitochondrial Impairment to Altered α-Synuclein Metabolism and Oxidative Damage
These studies indicate that chronic low-grade complex I inhibition caused by rotenone exposure induces accumulation and aggregation of α-synuclein and ubiquitin, progressive oxidative damage, and caspase-dependent death, mechanisms that may be central to PD pathogenesis.