The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders

Gennarini, Gianfranco; Bizzoca, Antonella; Picocci, Sabrina; Puzzo, Daniela; Corsi, Patrizia; Furley, Andrew J.

doi:10.1016/j.mcn.2016.11.006

Cited by 54 publications

(47 citation statements)

References 243 publications

(189 reference statements)

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“…38 The contact in 1 protein, encoded by CNTN1 , is a glycosylphosphatidylinositol-anchored neuronal membrane protein that functions as a cell-adhesion molecule with important roles in axonal function. 39,40 Mutations in CNTN1 were found to cause a familial form of lethal congenital myopathy. 41 Contactin 1 drives Notch-signalling activation and modulates neuroinflammation events, possibly participating in the pathogenesis of multiple sclerosis and other inflammatory disorders.…”

Section: Discussionmentioning

confidence: 99%

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Guerreiro

Ross

Kun‐Rodrigues

et al. 2018

The Lancet Neurology

212

240

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Summary Background Dementia with Lewy bodies is the second most common form of dementia in elderly people but has been overshadowed in the research field, partly because of similarities between dementia with Lewy bodies, Parkinson’s disease, and Alzheimer’s disease. So far, to our knowledge, no large-scale genetic study of dementia with Lewy bodies has been done. To better understand the genetic basis of dementia with Lewy bodies, we have done a genome-wide association study with the aim of identifying genetic risk factors for this disorder. Methods In this two-stage genome-wide association study, we collected samples from white participants of European ancestry who had been diagnosed with dementia with Lewy bodies according to established clinical or pathological criteria. In the discovery stage (with the case cohort recruited from 22 centres in ten countries and the controls derived from two publicly available database of Genotypes and Phenotypes studies [phs000404.v1.p1 and phs000982.v1.p1] in the USA), we performed genotyping and exploited the recently established Haplotype Reference Consortium panel as the basis for imputation. Pathological samples were ascertained following autopsy in each individual brain bank, whereas clinical samples were collected after participant examination. There was no specific timeframe for collection of samples. We did association analyses in all participants with dementia with Lewy bodies, and also only in participants with pathological diagnosis. In the replication stage, we performed genotyping of significant and suggestive results from the discovery stage. Lastly, we did a meta-analysis of both stages under a fixed-effects model and used logistic regression to test for association in each stage. Findings This study included 1743 patients with dementia with Lewy bodies (1324 with pathological diagnosis) and 4454 controls (1216 patients with dementia with Lewy bodies vs 3791 controls in the discovery stage; 527 vs 663 in the replication stage). Results confirm previously reported associations: APOE (rs429358; odds ratio [OR] 2·40, 95% CI 2·14–2·70; p=1·05 × 10−48), SNCA (rs7681440; OR 0·73, 0·66–0·81; p=6·39 × 10−10), and GBA (rs35749011; OR 2·55, 1·88–3·46; p=1·78 × 10−9). They also provide some evidence for a novel candidate locus, namely CNTN1 (rs7314908; OR 1·51, 1·27–1·79; p=2·32 × 10−6); further replication will be important. Additionally, we estimate the heritable component of dementia with Lewy bodies to be about 36%. Interpretation Despite the small sample size for a genome-wide association study, and acknowledging the potential biases from ascertaining samples from multiple locations, we present the most comprehensive and well powered genetic study in dementia with Lewy bodies so far. These data show that common genetic variability has a role in the disease.

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Section: Discussionmentioning

confidence: 99%

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Guerreiro

Ross

Kun‐Rodrigues

et al. 2018

The Lancet Neurology

212

240

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“…A subset of this family is the glycosyl-phosphatidyl inositol (GPI) anchored glycoproteins, Contactins (Gennarini et al, 2017). Contactins have C2-type Ig domains at their amino terminus and Fibronectin type III domains proximal to the plasma membrane.…”

Section: Control Of Maturation By Pet-1mentioning

confidence: 99%

Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function

Spencer

Deneris

2017

Front. Cell. Neurosci.

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The brain serotonin (5-hydroxytryptamine; 5-HT) system has been extensively studied for its role in normal physiology and behavior, as well as, neuropsychiatric disorders. The broad influence of 5-HT on brain function, is in part due to the vast connectivity pattern of 5-HT-producing neurons throughout the CNS. 5-HT neurons are born and terminally specified midway through embryogenesis, then enter a protracted period of maturation, where they functionally integrate into CNS circuitry and then are maintained throughout life. The transcriptional regulatory networks controlling progenitor cell generation and terminal specification of 5-HT neurons are relatively well-understood, yet the factors controlling 5-HT neuron maturation are only recently coming to light. In this review, we first provide an update on the regulatory network controlling 5-HT neuron development, then delve deeper into the properties and regulatory strategies governing 5-HT neuron maturation. In particular, we discuss the role of the 5-HT neuron terminal selector transcription factor (TF) Pet-1 as a key regulator of 5-HT neuron maturation. Pet-1 was originally shown to positively regulate genes needed for 5-HT synthesis, reuptake and vesicular transport, hence 5-HT neuron-type transmitter identity. It has now been shown to regulate, both positively and negatively, many other categories of genes in 5-HT neurons including ion channels, GPCRs, transporters, neuropeptides, and other transcription factors. Its function as a terminal selector results in the maturation of 5-HT neuron excitability, firing characteristics, and synaptic modulation by several neurotransmitters. Furthermore, there is a temporal requirement for Pet-1 in the control of postmitotic gene expression trajectories thus indicating a direct role in 5-HT neuron maturation. Proper regulation of the maturation of cellular identity is critical for normal neuronal functioning and perturbations in the gene regulatory networks controlling these processes may result in long-lasting changes in brain function in adulthood. Further study of 5-HT neuron gene regulatory networks is likely to provide additional insight into how neurons acquire their mature identities and how terminal selector-type TFs function in postmitotic vertebrate neurons.

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“…TREM2 variants have been associated with early‐onset dementia, and they may impair autophagy and clearance of misfolded proteins . CNTN1 encodes contactin 1 that modulates remyelination and neuroinflammation and regulates the activity of APP cleaving enzyme BACE1 . NOS2 generates nitric oxide in neurons and microglia, and it promotes cell survival though inhibition of apoptosis .…”

Section: Discussionmentioning

confidence: 99%

Systematic review of genetic association studies in people with Lewy body dementia

Sanghvi

Singh

Morrin

et al. 2020

Int J Geriat Psychiatry

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Objectives Lewy body dementia (LBD) causes more morbidity, disability, and earlier mortality than Alzheimer disease. Molecular mechanisms underlying neurodegeneration in LBD are poorly understood. We aimed to do a systematic review of all genetic association studies that investigated people with LBD for improving our understanding of LBD molecular genetics and for facilitating discovery of novel biomarkers and therapeutic targets for LBD. Methods We systematically reviewed five online databases (PROSPERO protocol: CRD42018087114) and completed the quality assessment using the quality of genetic association studies tool. Results Eight thousand five hundred twenty‐one articles were screened, and 75 articles were eligible to be included. Genetic associations of LBD with APOE, GBA, and SNCA variants have been replicated by two or more good quality studies. Our meta‐analyses confirmed that APOE‐ε4 is significantly associated with dementia with Lewy bodies (pooled odds ratio [POR] = 2.70; 95% CI, 2.37‐3.07; P < .001) and Parkinson's disease dementia (POR = 1.60; 95% CI, 1.21‐2.11; P = .001). Other reported genetic associations that need further replication include variants in A2M, BCHE‐K, BCL7C, CHRFAM7A, CNTN1, ESR1, GABRB3, MAPT, mitochondrial DNA (mtDNA) haplogroup H, NOS2A, PSEN1, SCARB2, TFAM, TREM2, and UCHL1. Conclusions The reported genetic associations and their potential interactions indicate the importance of α‐synuclein, amyloid, and tau pathology, autophagy lysosomal pathway, ubiquitin proteasome system, oxidative stress, and mitochondrial dysfunction in LBD. There is a need for larger genome‐wide association study (GWAS) for identifying more LBD‐associated genes. Future hypothesis‐driven studies should aim to replicate reported genetic associations of LBD and to explore their functional implications.

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The role of Gpi-anchored axonal glycoproteins in neural development and neurological disorders

Cited by 54 publications

References 243 publications

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Investigating the genetic architecture of dementia with Lewy bodies: a two-stage genome-wide association study

Regulatory Mechanisms Controlling Maturation of Serotonin Neuron Identity and Function

Systematic review of genetic association studies in people with Lewy body dementia

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