Genetic, Structural, and Functional Evidence Link <i>TMEM175</i> to Synucleinopathies

Krohn, Lynne; Öztürk, Tuğba N.; Vanderperre, Benoît; Bencheikh, Bouchra Ouled Amar; Ruskey, Jennifer A.; Laurent, Sandra B.; Spiegelman, Dan; Postuma, Ronald B.; Arnulf, Isabelle; Hu, Michele T.M.; Dauvilliers, Yves; Högl, Birgit; Stefani, Ambra; Monaca, Christelle; Plazzi, Giuseppe; Antelmi, Elena; Ferini‐Strambi, Luigi; Heidbreder, Anna; Rudakou, Uladzislau; Cock, Valérie Cochen De; Young, Peter; Wolf, Pavlina; Oliva, Petra; Zhang, Xiaokui Kate; Greenbaum, Lior; Liong, Christopher; Gagnon, Jean François; Désautels, Alex; Hassin‐Baer, Sharon; Montplaisir, Jacques; Dupré, Nicolas; Rouleau, Guy A.; Fon, Edward A.; Trempe, Jean François; Lamoureux, Guillaume; Alcalay, Roy N.

doi:10.1002/ana.25629

Cited by 82 publications

(77 citation statements)

References 49 publications

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“…17 More recently, it was demonstrated that the PD-associated TMEM175 coding variant p.M393T was associated with RBD and potentially affects the activity of the lysosomal enzyme glucocerebrosidase (encoded by GBA). 15,54 Therefore, it is possible that some genetic variants are relevant for all types of synucleinopathy, with and without RBD, but other variants are specifically relevant for RBD-associated synucleinopathy. Currently, the division between PD and DLB is somewhat arbitrary, determined by a cutoff of one year between the onset of parkinsonism and the onset of dementia.…”

Section: Discussionmentioning

confidence: 99%

Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

Krohn

Heilbron

et al. 2020

Annals of Neurology

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Objective Rapid eye movement sleep behavior disorder (RBD) is a prodromal synucleinopathy, as >80% will eventually convert to overt synucleinopathy. We performed an in‐depth analysis of the SNCA locus to identify RBD‐specific risk variants. Methods Full sequencing and genotyping of SNCA was performed in isolated/idiopathic RBD (iRBD, n = 1,076), Parkinson disease (PD, n = 1,013), dementia with Lewy bodies (DLB, n = 415), and control subjects (n = 6,155). The iRBD cases were diagnosed with RBD prior to neurodegeneration, although some have since converted. A replication cohort from 23andMe of PD patients with probable RBD (pRBD) was also analyzed (n = 1,782 cases; n = 131,250 controls). Adjusted logistic regression models and meta‐analyses were performed. Effects on conversion rate were analyzed in 432 RBD patients with available data using Kaplan–Meier survival analysis. Results A 5′‐region SNCA variant (rs10005233) was associated with iRBD (odds ratio [OR] = 1.43, p = 1.1E‐08), which was replicated in pRBD. This variant is in linkage disequilibrium (LD) with other 5′ risk variants across the different synucleinopathies. An independent iRBD‐specific suggestive association (rs11732740) was detected at the 3′ of SNCA (OR = 1.32, p = 4.7E‐04, not statistically significant after Bonferroni correction). Homozygous carriers of both iRBD‐specific SNPs were at highly increased risk for iRBD (OR = 5.74, p = 2E‐06). The known top PD‐associated variant (3′ variant rs356182) had an opposite direction of effect in iRBD compared to PD. Interpretation There is a distinct pattern of association at the SNCA locus in RBD as compared to PD, with an opposite direction of effect at the 3′ of SNCA. Several 5′ SNCA variants are associated with iRBD and with pRBD in overt synucleinopathies. ANN NEUROL 2020;87:584–598

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Section: Discussionmentioning

confidence: 99%

Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

Krohn

Heilbron

et al. 2020

Annals of Neurology

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“…The propagation of α-syn in PD patients with GBA risk variants alongside the reduced efficiency of α-syn degradation may therefore be accompanied by some perturbations in the immune system. It is known that the GCase activity is regulated by other factors than just the gene encoding the enzyme itself and recently, it has been suggested that some variants of the TMEM175 gene that encodes a potassium pump regulating lysosomal pH may also affect the PD risk by affecting the GCase activity [97,98]. A recent study also demonstrated that the PD onset in GBA variant carriers could be modified by the presence of variants in the SNCA and CTSB loci, and the latter may further exacerbate the lysosomal dysfunction by causing a deficiency in the lysosomal protease cathepsin B [99].…”

Section: Drug Trials Targeting Gba Impairments In Pdmentioning

confidence: 99%

Precision medicine in Parkinson’s disease patients with LRRK2 and GBA risk variants – Let’s get even more personal

Linstow

Gan‐Or

Brundin

2020

Transl Neurodegener

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Parkinson’s disease (PD) is characterized by motor deficits and a wide variety of non-motor symptoms. The age of onset, rate of disease progression and the precise profile of motor and non-motor symptoms display considerable individual variation. Neuropathologically, the loss of substantia nigra dopaminergic neurons is a key feature of PD. The vast majority of PD patients exhibit alpha-synuclein aggregates in several brain regions, but there is also great variability in the neuropathology between individuals. While the dopamine replacement therapies can reduce motor symptoms, current therapies do not modify the disease progression. Numerous clinical trials using a wide variety of approaches have failed to achieve disease modification. It has been suggested that the heterogeneity of PD is a major contributing factor to the failure of disease modification trials, and that it is unlikely that a single treatment will be effective in all patients. Precision medicine, using drugs designed to target the pathophysiology in a manner that is specific to each individual with PD, has been suggested as a way forward. PD patients can be stratified according to whether they carry one of the risk variants associated with elevated PD risk. In this review we assess current clinical trials targeting two enzymes, leucine-rich repeat kinase 2 (LRRK2) and glucocerebrosidase (GBA), which are encoded by two most common PD risk genes. Because the details of the pathogenic processes coupled to the different LRRK2 and GBA risk variants are not fully understood, we ask if these precision medicine-based intervention strategies will prove “precise” or “personalized” enough to modify the disease process in PD patients. We also consider at what phases of the disease that such strategies might be effective, in light of the genes being primarily associated with the risk of developing disease in the first place, and less clearly linked to the rate of disease progression. Finally, we critically evaluate the notion that therapies targeting LRRK2 and GBA might be relevant to a wider segment of PD patients, beyond those that actually carry risk variants of these genes.

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“…However, it is unclear which gene or genes are responsible for this association. Several recent papers suggest that coding variants in TMEM175 43 , eQTL affecting GAK 42 , IDUA and DGKQ 44 or CPLX1 45 could be the drivers of this association. We found that the SNPs in this locus were associated with IDUA protein levels as well as Parkinson's disease risk (rs35220088; p= 2.47×10 -6 and 3.52×10 -9 , respectively) and our MR analyses indicate that IDUA is a functional gene in this locus.…”

Section: Mendelian Randomization To Identify Novel Biomarkers and Drumentioning

confidence: 99%

Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits

Cruchaga¹,

Yang²,

Farias³

et al. 2020

Preprint

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Understanding the tissue-specific genetic architecture of protein levels is instrumental to understand the biology of health and disease. We generated a genomic atlas of protein levels in multiple neurologically relevant tissues (380 brain, 835 cerebrospinal fluid (CSF) and 529 plasma), by profiling thousands of proteins (713 CSF, 931 plasma and 1079 brain) in a large and well-characterized cohort. We identified 274, 127 and 32 protein quantitative loci (pQTL) for CSF, plasma and brain respectively. cis-pQTL were more likely to be shared across tissues but trans-pQTL tend to be tissue-specific. Between 44% to 68.2% of the pQTL do not colocalize with expression, splicing, methylation or histone QTLs, indicating that protein levels have a different genetic architecture to those that regulate gene expression. By combining our pQTL with Mendelian Randomization approaches we identified potential novel biomarkers and drug targets for neurodegenerative diseases including Alzheimer disease and frontotemporal dementia. Here we present the first multi-tissue study yielding hundred of novel pQTLs. This data will be instrumental to identify the functional gene from GWAS signals, identify novel biological protein-protein interactions, identify novel potential biomarkers and drug targets for complex traits.

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Genetic, Structural, and Functional Evidence Link TMEM175 to Synucleinopathies

Cited by 82 publications

References 49 publications

Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

Fine‐Mapping of SNCA in Rapid Eye Movement Sleep Behavior Disorder and Overt Synucleinopathies

Precision medicine in Parkinson’s disease patients with LRRK2 and GBA risk variants – Let’s get even more personal

Genomic and multi-tissue proteomic integration for understanding the biology of disease and other complex traits

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