An updated review of Parkinson's disease genetics and clinicopathological correlations

Ferreira, Mariana; Massano, João

doi:10.1111/ane.12616

Cited by 142 publications

(114 citation statements)

References 117 publications

(190 reference statements)

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“…On the other hand, increasing evidence has suggested that a genetic factor has a strong impact on the pathogenesis of PD. Indeed, in the past two decades, more than 20 genes have been identified as causal and/or risk genes for PD (Ferreira and Massano 2017). In particular, the implication of αSYN as a culprit of PD-linked neuropathology expanded enormously when the SNCA gene (PARK1), which encodes αSYN, was identified as the first PD-related gene (Polymeropoulos et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Membrane Trafficking Illuminates a Path to Parkinson’s Disease

Hasegawa

Sugeno

Kikuchi

et al. 2017

Tohoku J. Exp. Med.

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Parkinson's disease (PD) is the second most common neurodegenerative disorder that is characterized by progressive movement disability and a variety of non-motor symptoms. The neuropathology of PD consists of the loss of dopaminergic neurons in the midbrain and the appearance of neuronal inclusions called Lewy bodies, which contain insoluble α-synuclein, a relatively small protein originally identified in association with synaptic vesicles in the presynaptic nerve terminals. Drugs that replenish dopamine can partly alleviate the motor symptoms, but they do not cure the disease itself. Therefore, there is an urgent need for disease modification in terms of the delay or prevention of neurodegeneration. Recent advances in genetic and biochemical studies have provided unifying conceptual frameworks of the pathogenesis of PD. Particularly, membrane trafficking has aroused special attention as an initiator or enhancer of the neurodegenerative process that leads to PD. Defects in the cellular trafficking pathway result in synaptic dysfunction and the accumulation of misfolded α -synuclein. Likewise, changes in intracellular sorting and degradation profoundly influence the cellular trafficking of misfolded proteins, thereby facilitating the cell-to-cell spreading of hazardous α-synuclein species in a prion-like manner. Here, we will review our current knowledge of the functional roles of membrane trafficking in PD and will discuss how this cellular process could induce or facilitate the functional and pathological alterations in this disease.

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Section: Introductionmentioning

confidence: 99%

Membrane Trafficking Illuminates a Path to Parkinson’s Disease

Hasegawa

Sugeno

Kikuchi

et al. 2017

Tohoku J. Exp. Med.

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“…α-Synuclein is a major PD-causative gene, and missense mutations and gene multiplication, or excessive phosphorylation of α-synuclein by GRK5 and GRK6 promotes its deposition in Lewy bodies. 2,7,8) EIF4G1 is ubiquitous and abundantly expressed in various tissues. It operates as a scaffold protein that interacts with many translation initiation factors.…”

Section: Resultsmentioning

confidence: 99%

“…Approximately 10% of PD is familial, and many causative genes have been identified. [1][2][3] However, the other 90% of PD occurs sporadically and its causes are poorly understood.…”

mentioning

confidence: 99%

Transcriptome Analysis Reveals That Midnolin Regulates mRNA Expression Levels of Multiple Parkinson’s Disease Causative Genes

Obara

Ishii

2018

Biological & Pharmaceutical Bulletin

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We recently found that 10.5% of sporadic Parkinson's disease (PD) patients lacked one copy of the midnolin (MIDN) gene. In addition, gene knock-down/out of MIDN caused down-regulation of parkin E3 ubiquitin ligase, indicating MIDN to be a novel PD-risk factor or causative gene. In this study, we performed RNA-sequencing and transcriptome analysis of Midn wild-type and knockout cells. Midn positively or negatively regulated the expression of a wide variety of genes, including causative familial PD genes, such as α-synuclein, parkin, and EIF4G1. However, EIF4G1 protein levels were not altered by the reduction of its mRNA by Midn loss, as seen that parkin protein levels were correlated to the mRNA down-regulation. Taken together, these findings indicate that MIDN regulates the expression of a wide variety of genes, including multiple PD-causative genes and is associated with PD onset. Key words midnolin (MIDN); Parkinson's disease (PD); transcriptome analysis; parkinParkinson's disease (PD) is a progressive neurodegenerative disease accompanied by loss of dopaminergic neurons in the substantia nigra region of the midbrain, which projects to the striatum, resulting in an extrapyramidal disorder. Approximately 10% of PD is familial, and many causative genes have been identified.1-3) However, the other 90% of PD occurs sporadically and its causes are poorly understood.Midnolin (Midn) was discovered using a gene trap approach in embryonic stem cells. 4) MIDN is strongly expressed in the midbrain, and is localized to the nucleus and nucleolus. However, its expression is not limited to the midbrain and it is widely expressed in major organs.4) MIDN interacts with glucokinase via an N-terminal ubiquitin-like domain with high homology to parkin ubiquitin E3 ligase, leading to a significant reduction in glucokinase activity and glucose-induced insulin secretion from MIN6 cells. 5) Overall, although MIDN was discovered many years ago, its pathophysiological roles remain unclear.We recently showed that MIDN expression is induced by nerve growth factor (NGF) in PC12 cells, a model rat cell line for catecholaminergic neurons and that NGF-stimulated neurite outgrowth is attenuated in MIDN-deficient cells.6) However, tyrosine hydroxylase protein levels were not significantly altered in the study, indicating MIDN may not be involved in catecholamine biosynthesis in these cells. 6) Surprisingly, 10.5% of patients with sporadic PD lacked one copy of the MIDN gene whereas no copy number variation was observed in healthy people, suggesting MIDN to be a novel PD-risk factor or causative gene. Moreover, parkin (Park2), a familial PD-causative gene, was down-regulated by Midn knockout/ down in PC12 cells. 6) MIDN is assumed to be a transcription modulator; therefore, examination of expression of other PDrelated genes in Midn-manipulated cells is warranted. Thus, a comprehensive transcriptome analysis was performed in wildtype and Midn-knockout PC12 cells. MATERIALS AND METHODSMIDN-positive and -negative PC12 cells were grown in Dulbecco'...

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“…For reasons of space, this review does not include new results on PD genes identified before 2012, where new results acquired in recent years have consolidated, expanded, and sometimes refuted previous knowledge. Readers are referred to broader previous reviews that summarize the knowledge in the field available at the time of their writing [1–6]. …”

Section: Introductionmentioning

confidence: 99%

New Genes Causing Hereditary Parkinson’s Disease or Parkinsonism

Puschmann

2017

Curr Neurol Neurosci Rep

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Purpose of ReviewThis article reviews genes where putative or confirmed pathogenic mutations causing Parkinson’s disease or Parkinsonism have been identified since 2012, and summarizes the clinical and pathological picture of the associated disease subtypes.Recent FindingsNewly reported genes for dominant Parkinson’s disease are DNAJC13, CHCHD2, and TMEM230. However, the evidence for a disease-causing role is not conclusive, and further genetic and functional studies are warranted. RIC3 mutations have been reported from one family but not yet encountered in other patients. New genes for autosomal recessive disease include SYNJ1, DNAJC6, VPS13C, and PTRHD1. Deletions of a region on chromosome 22 (22q11.2del) are also associated with early-onset PD, but the mode of inheritance and the underlying causative gene remain unclear. PODXL mutations were reported in autosomal recessive PD, but their roles remain to be confirmed. Mutations in RAB39B cause an X-linked Parkinsonian disorder. SummaryMutations in the new dominant PD genes have generally been found in medium- to late-onset Parkinson’s disease. Many mutations in the new recessive and X-chromosomal genes cause severe atypical juvenile Parkinsonism, but less devastating mutations in these genes may cause PD.

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An updated review of Parkinson's disease genetics and clinicopathological correlations

Cited by 142 publications

References 117 publications

Membrane Trafficking Illuminates a Path to Parkinson’s Disease

Membrane Trafficking Illuminates a Path to Parkinson’s Disease

Transcriptome Analysis Reveals That Midnolin Regulates mRNA Expression Levels of Multiple Parkinson’s Disease Causative Genes

New Genes Causing Hereditary Parkinson’s Disease or Parkinsonism

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