The genetics of Parkinson's syndromes: a critical review

Hardy, John; Lewis, Patrick A.; Révész, Tamás; Lees, Andrew J.; Paisán-Ruı́z, Coro

doi:10.1016/j.gde.2009.03.008

Cited by 195 publications

(146 citation statements)

References 94 publications

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“…In humans, the degeneration of the DA neurons of the midbrain substantia nigra (A9) leads to Parkinson's disease (PD), which is the second most common neurodegenerative disease [1]. Great efforts are in place to understand the molecular mechanisms that trigger PD, taking advantage of human genetics [2] and animal modeling [3,4]. However, a better comprehension of PD pathological mechanisms would certainly be accelerated if a renewable culture system of human DA neurons were accessible.…”

Section: Introductionmentioning

confidence: 99%

Rapid Generation of Functional Dopaminergic Neurons From Human Induced Pluripotent Stem Cells Through a Single-Step Procedure Using Cell Lineage Transcription Factors

Theka

Caiazzo

Dvoretskova

et al. 2013

Stem Cells Translational Medicine

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Current protocols for in vitro differentiation of human induced pluripotent stem cells (hiPSCs) to generate dopamine (DA) neurons are laborious and time-expensive. In order to accelerate the overall process, we have established a fast protocol by expressing the developmental transcription factors ASCL1, NURR1, and LMX1A. With this method, we were able to generate mature and functional dopaminergic neurons in as few as 21 days, skipping all the intermediate steps for inducting and selecting embryoid bodies and rosette-neural precursors. Strikingly, the resulting neuronal conversion process was very proficient, with an overall efficiency that was more than 93% of all the coinfected cells. hiPSC-derived DA neurons expressed all the critical molecular markers of the DA molecular machinery and exhibited sophisticated functional features including spontaneous electrical activity and dopamine release. This one-step protocol holds important implications for in vitro disease modeling and is particularly amenable for exploitation in high-throughput screening protocols. STEM CELLS TRANSLATIONAL MEDICINE 2013;2:473-479

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Section: Introductionmentioning

confidence: 99%

Rapid Generation of Functional Dopaminergic Neurons From Human Induced Pluripotent Stem Cells Through a Single-Step Procedure Using Cell Lineage Transcription Factors

Theka

Caiazzo

Dvoretskova

et al. 2013

Stem Cells Translational Medicine

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“…1 Although the majority of PD is idiopathic, pathogenic mutations have successfully been identified in some mendelian forms. 2 Many of these mendelian genes have also been investigated in the idiopathic disease, but only SNPs at the SNCA and LRRK2 loci have shown susceptibility for idiopathic PD (IPD): several SNPs at the SNCA locus have been characterized as risk factors for IPD in different populations, 3 a LRRK2-associated haplotype showed an increased disease risk in the Chinese population, 4 two LRRK2 mutations absent in European ancestry populations are overrepresented in PD in some Asian populations 5,6 and common LRRK2 variation may also contribute to the risk for IPD in the North American population. 7 Similarly, the frequency and distribution of GBA mutations in PD vary within populations, being more prevalent among the Ashkenazi Jewish population and rare among Asians.…”

Section: Introductionmentioning

confidence: 99%

Genetic variability at the PARK16 locus

Tucci¹,

Nalls

Houlden³

et al. 2010

Eur J Hum Genet

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Parkinson's disease (PD) is a complex neurodegenerative disease which is clinically heterogeneous and pathologically consists of loss of dopaminergic neurons in the substantia nigra and intracytoplasmic neuronal inclusions containing alpha-synuclein aggregations known as Lewy bodies. Although the majority of PD is idiopathic, pathogenic mutations in several mendelian genes have been successfully identified through linkage analyses. To identify susceptibility loci for idiopathic PD, several genome-wide association studies (GWAS) within different populations have recently been conducted in both idiopathic and familial forms of PD. These analyses have confirmed SNCA and MAPT as loci harboring PD susceptibility. In addition, the GWAS identified several other genetic loci suggestively associated with the risk of PD; among these, only one was replicated by two different studies of European and Asian ancestries. Hence, we investigated this novel locus known as PARK16 for coding mutations in a large series of idiopathic pathologically proven PD cases, and also conducted an association study in a case-control cohort from the United Kingdom. An association between a novel RAB7L1 mutation, c.379-12insT, and disease (P-value¼0.0325) was identified. Two novel coding variants present only in the PD cohort were also identified within the RAB7L1 (p.K157R) and SLC41A1 (p.A350V) genes. No copy number variation analyses have yet been performed within this recently identified locus. We concluded that, although both coding variants and risk alleles within the PARK16 locus seem to be rare, further molecular analyses within the PARK16 locus and within different populations are required in order to examine its biochemical role in the disease process.

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“…Overexpression of either WT or mutant α-synuclein in transgenic mice causes age-related neurodegeneration (13)(14)(15). Although patients carrying recessively inherited mutations in Parkin often do not have Lewy bodies (no reports of postmortem studies on DJ-1 and PINK1 yet), PD patients bearing mutations in α-synuclein or LRRK2 typically have Lewy bodies in nigral neurons (16).…”

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confidence: 99%

Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

Tong

Yamaguchi

Giaime

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

468

499

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Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common genetic cause of Parkinson's disease. LRRK2 is a large protein containing a small GTPase domain and a kinase domain, but its physiological role is unknown. To identify the normal function of LRRK2 in vivo, we generated two independent lines of germ-line deletion mice. The dopaminergic system of LRRK2 −/− mice appears normal, and numbers of dopaminergic neurons and levels of striatal dopamine are unchanged. However, LRRK2 −/− kidneys, which suffer the greatest loss of LRRK compared with other organs, develop striking accumulation and aggregation of α-synuclein and ubiquitinated proteins at 20 months of age. The autophagy-lysosomal pathway is also impaired in the absence of LRRK2, as indicated by accumulation of lipofuscin granules as well as altered levels of LC3-II and p62. Furthermore, loss of LRRK2 dramatically increases apoptotic cell death, inflammatory responses, and oxidative damage. Collectively, our findings show that LRRK2 plays an essential and unexpected role in the regulation of protein homeostasis during aging, and suggest that LRRK2 mutations may cause Parkinson's disease and cell death via impairment of protein degradation pathways, leading to α-synuclein accumulation and aggregation over time.Parkinson's disease | knockout | autophagy | ubiquitin-proteasome system | aging P arkinson's disease (PD) is the most common movement disorder. The neuropathological hallmarks of PD are progressive degeneration of dopaminergic (DA) neurons and the presence of intraneuronal cytoplasmic inclusions known as Lewy bodies, of which α-synuclein is a major constituent (1). Dominantly inherited mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial PD (2, 3), highlighting the importance of LRRK2 in PD pathogenesis; however, the normal physiological role of LRRK2 is unknown. LRRK2 is a large protein containing a Ras-like small GTPase domain and a MAPKKK-like kinase domain, and has a functional homolog LRRK1, which shares similar domain structures (4). Crystal structural and biochemical studies showed that the GTPase domain forms a dimer; the pathogenic mutations destabilize the dimer and reduce GTPase activity (5-7). A recent in vitro study suggested that LRRK2 and LRRK1 can interact with each other and form a heterodimer (8). Although no physiological substrate of the LRRK2 kinase activity has been reported, studies in cultured cells have suggested that some pathogenic mutations in LRRK2 cause increases in LRRK2 kinase activity (9, 10).Protein aggregation is thought to play a major role in neurodegeneration and PD pathogenesis (11). The strongest evidence came from studies of α-synuclein. Gene multiplication and missense mutations in α-synuclein have been identified in early-onset familial PD with dominant inheritance (12). α-Synuclein is a major constituent of Lewy bodies (1). Overexpression of either WT or mutant α-synuclein in transgenic mice causes age-related neurodegeneration (13-15). Although patients carryi...

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The genetics of Parkinson's syndromes: a critical review

Cited by 195 publications

References 94 publications

Rapid Generation of Functional Dopaminergic Neurons From Human Induced Pluripotent Stem Cells Through a Single-Step Procedure Using Cell Lineage Transcription Factors

Rapid Generation of Functional Dopaminergic Neurons From Human Induced Pluripotent Stem Cells Through a Single-Step Procedure Using Cell Lineage Transcription Factors

Genetic variability at the PARK16 locus

Loss of leucine-rich repeat kinase 2 causes impairment of protein degradation pathways, accumulation of α-synuclein, and apoptotic cell death in aged mice

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