Unraveling the pathogenesis of Parkinson?s disease ? the contribution of monogenic forms

Bonifati, Vincenzo; Oostra, Ben A.; Heutink, Peter

doi:10.1007/s00018-004-4104-1

Cited by 48 publications

(27 citation statements)

References 260 publications

(401 reference statements)

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“…However, in some cases the disease is inherited as a highly penetrant Mendelian trait, and the identification of families with monogenic forms of PD has been determinant for the recent progress in the understanding of the molecular mechanisms. 1,2 Mutations in five genes have been firmly implicated in the aetiology of PD. Mutations in the SNCA 3,4 gene, encoding the a-synuclein protein, cause autosomal dominant forms, whereas mutations in the PARK2, 5 , PARK7, 6 and PINK1, 7 gene, encoding the parkin, DJ-1, and PINK1 protein, respectively, cause autosomal recessive forms.…”

Section: Introductionmentioning

confidence: 99%

“…Additional loci for mendelian and more complex forms have been mapped, but the defective genes have not been identified yet. 1 A different locus, PARK8 (MIM #607 060), was first mapped to chromosome 12 in a Japanese family with dominantly inherited parkinsonism. 8 Recently, mutations in the gene leucine-rich repeat kinase 2 (LRRK2) (MIM *609 007) have been identified in PARK8-linked families.…”

Section: Introductionmentioning

confidence: 99%

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Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease

et al. 2005

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Mutations in the gene leucine-rich repeat kinase 2 (LRRK2) have been recently identified in families with Parkinson's disease (PD). However, the prevalence and nature of LRRK2 mutations, the polymorphism content of the gene, and the associated phenotypes remain poorly understood. We performed a comprehensive study of this gene in a large sample of families with Parkinson's disease compatible with autosomal dominant inheritance (ADPD). The full-length open reading frame and splice sites of the LRRK2 gene (51 exons) were studied by genomic sequencing in 60 probands with ADPD (83% Italian). Pathogenic mutations were identified in six probands (10%): the heterozygous p.G2019S mutation in four (6.6%), and the heterozygous p.R1441C mutation in two (3.4%) probands. A further proband carried the heterozygous p.I1371 V mutation, for which a pathogenic role could not be established with certainty. In total, 13 novel disease-unrelated variants and three intronic changes of uncertain significance were also characterized. The phenotype associated with LRRK2 pathogenic mutations is the one of typical PD, but with a broad range of onset ages (mean 55.2, range 38-68 years) and, in some cases, slow disease progression. On the basis of the comprehensive study in a large sample, we conclude that pathogenic LRRK2 mutations are frequent in ADPD, and they cluster in the C-terminal half of the encoded protein. These data have implications both for understanding the molecular mechanisms of PD, and for directing the genetic screening in clinical practice.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease

et al. 2005

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“…Parkinson's disease (PD) is a multi-system disorder characterized by the involvement of selected neuronal populations throughout the central and peripheral nervous systems [3,6]. The pathological hallmark of PD is the degeneration of dopaminergic, melanized neurons of the substantia nigra pars compacta (SNc) projecting to the striatum, which triggers the motor symptoms of the disease (tremor, rigidity and bradykinesia) [5].…”

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confidence: 99%

Functional and neurochemical changes of the gastrointestinal tract in a rodent model of Parkinson's disease

Blandini¹,

Balestra

Levandis³

et al. 2009

Neuroscience Letters

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a b s t r a c tPatients with Parkinson's disease develop motor disturbances often accompanied by peripheral autonomic dysfunctions, including gastrointestinal disorders, such as dysphagia, gastric stasis and constipation. While the mechanisms subserving enteric autonomic dysfunctions are not clearly understood, they may involve the enteric dopaminergic and/or nitrergic systems. In the present study, we demonstrate that rats with unilateral 6-hydroxydopamine lesion of nigrostriatal dopaminergic neurons develop a marked inhibition of propulsive activity compared to sham-operated controls, as indicated by a 60% reduction of daily fecal output at the 4th week of observation. Immunohistochemical data revealed that 6-hydroxydopamine treatment did not affect the total number of HuC/D-positive myenteric neurons in both the proximal and distal segments of ileum and colon. Conversely, in the distal ileum and proximal colon the number of nitrergic neurons was significantly reduced. These results suggest that a disturbed distal gut transit, reminiscent of constipation in the clinical setting, may occur as a consequence of a reduced propulsive motility, likely due to an impairment of a nitric oxide-mediated descending inhibition during peristalsis.

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“…In addition to sporadic forms of PD, there are various familial forms of the disease that altogether account for 15% of PD cases, including those linked to mutations of the a-synuclein gene, for a total of 13 different genes or loci associated with PD [21][22][23][24][25][26]. Autosomal recessive forms of Parkinsonism are linked to mutations in the Parkin (PARK2, the most common), PINK1 (PARK6), and DJ-1 (PARK7) genes, and are characterized by early onset of the disease.…”

Section: Introductionmentioning

confidence: 99%

The proteomic approach in Parkinson's disease

Fasano

Bergamasco

Lopiano

2007

Proteomics Clinical Apps

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Parkinson's disease (PD) is a complex, multifactorial neurodegenerative disease affecting about 2% of the population over 65 years. Etiopathogenetic mechanisms of PD are not fully understood, although a number of factors contributing to the selective degeneration of substantia nigra neurons have been identified, including mitochondrial dysfunction, proteasomal impairment, oxidative stress, excitotoxicity, and inflammation. Although a global view of the disease at the molecular level can be obtained only from the biochemical analysis of the affected human tissue, difficulties in obtaining human specimens of the affected area have limited substantially the number of reports published to date. Therefore, cellular and animal models of the disease have been developed to investigate single factors contributing to disease pathogenesis, e.g., protein aggregation or altered dopamine homeostasis. In this review, we report how proteomic methodologies have been used so far to investigate cellular and animal models of PD, as well as to compare postmortem specimens of substantia nigra of affected patients to that of control subjects. Proteomic studies concur to highlight the role of a compromised antioxidant defense in PD pathogenesis. The proteomic approach in the investigation of etiopathogenetic mechanisms of PD is still at its beginning, however, the findings reviewed here should serve as a useful foundation to further work.

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Unraveling the pathogenesis of Parkinson?s disease ? the contribution of monogenic forms

Cited by 48 publications

References 260 publications

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease

Comprehensive analysis of the LRRK2 gene in sixty families with Parkinson's disease

Functional and neurochemical changes of the gastrointestinal tract in a rodent model of Parkinson's disease

The proteomic approach in Parkinson's disease

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