TREM2 rare variant p.R47H is not associated with Parkinson's disease

Mengel, David; Thelen, M.; Balzer‐Geldsetzer, Monika; Söling, Charlotte; Bach, Jan-Philipp; Schaeffer, Eva; Herold, Christine; Becker, Tim; Liepelt, Inga; Becker, J.; Riedel‐Heller, Steffi G.; Scherer, Martin; Jessen, Frank; Maier, Wolfgang; Dodel, Richard; Ramı́rez, Alfredo

doi:10.1016/j.parkreldis.2015.11.026

Cited by 17 publications

(15 citation statements)

References 3 publications

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“…References shown in light green did find a significant association between the TREM2 variant and disease risk, but only in one or multiple populations they examined or only after inclusion of previously published literature into metastudy analyses. While these variants have been significantly associated with disease risk, many more studies find suggestive but not significant associations between additional TREM2 variants and NDD risk which are not represented here [ 5 , 6 , 16 , 18 , 26 , 28 , 30 , 31 , 35 – 37 , 39 – 42 , 45 – 47 , 49 – 52 , 54 , 55 , 57 , 58 , 60 , 64 , 65 , 67 , 70 , 82 , 83 , 88 , 131 , 323 – 325 ] …”

Section: Genetics Of Trem2 In Nddsmentioning

confidence: 82%

“…In amyotrophic lateral sclerosis (ALS), one study found a significant association of the R47H variant and ALS risk, as well as an inverse correlation between TREM2 levels in the spinal cord and survival in ALS patients [ 64 ], though this was not replicated by others [ 40 ]. The TREM2 R47H variant has also been reported to be associated with increased risk of Parkinson’s disease [ 39 ] by some [ 40 , 65 , 66 ] but not all studies [ 6 , 42 , 67 ]. In order to understand these differences, Lill and colleagues [ 42 ] divided their groups by ethnicity and found that the odds ratio of the R47H variant was significantly higher in their Northern European population compared to non-Northern Europeans.…”

Section: Genetics Of Trem2 In Nddsmentioning

confidence: 99%

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TREM2 in Neurodegenerative Diseases

Jay

Saucken

Landreth

2017

Mol Neurodegeneration

301

283

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TREM2 variants have been identified as risk factors for Alzheimer's disease (AD) and other neurodegenerative diseases (NDDs). Because TREM2 encodes a receptor exclusively expressed on immune cells, identification of these variants conclusively demonstrates that the immune response can play an active role in the pathogenesis of NDDs. These TREM2 variants also confer the highest risk for developing Alzheimer's disease of any risk factor identified in nearly two decades, suggesting that understanding more about TREM2 function could provide key insights into NDD pathology and provide avenues for novel immune-related NDD biomarkers and therapeutics. The expression, signaling and function of TREM2 in NDDs have been extensively investigated in an effort to understand the role of immune function in disease pathogenesis and progression. We provide a comprehensive review of our current understanding of TREM2 biology, including new insights into the regulation of TREM2 expression, and TREM2 signaling and function across NDDs. While many open questions remain, the current body of literature provides clarity on several issues. While it is still often cited that TREM2 expression is decreased by pro-inflammatory stimuli, it is now clear that this is true in vitro, but inflammatory stimuli in vivo almost universally increase TREM2 expression. Likewise, while TREM2 function is classically described as promoting an anti-inflammatory phenotype, more than half of published studies demonstrate a pro-inflammatory role for TREM2, suggesting that its role in inflammation is much more complex. Finally, these components of TREM2 biology are applied to a discussion of how TREM2 impacts NDD pathologies and the latest assessment of how these findings might be applied to immune-directed clinical biomarkers and therapeutics.

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Section: Genetics Of Trem2 In Nddsmentioning

confidence: 82%

Section: Genetics Of Trem2 In Nddsmentioning

confidence: 99%

TREM2 in Neurodegenerative Diseases

Jay

Saucken

Landreth

2017

Mol Neurodegeneration

301

283

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“…Since the p.R47H variant frequency varies across populations, it is imperative that, for this and other rare variants, association tests be performed only in sufficiently large and well-matched case-control groups 92 . In another study, a significant association between p.R47H and PD risk in a discovery cohort of North American patients diagnosed with PD and healthy controls was reported, but failed replication in that same study 89 The association of p.R47H with PD has subsequently failed independent replication in other association studies 33,93 . This association was also tested in the Chinese population and no significant effect on risk was found, again, with no variant being identified in this population [94][95][96][97] .…”

Section: Trem2 Genetic Variability In Other Neurodegenerative Diseasesmentioning

confidence: 98%

The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders

Carmona

Zahs

et al. 2018

The Lancet Neurology

190

144

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Alzheimer's disease is a genetically complex disorder; rare variants in the triggering receptor expressed on myeloid cells 2 (TREM2) gene have been shown to as much as triple an individual's risk of developing Alzheimer's disease. TREM2 is a transmembrane receptor expressed in cells of the myeloid lineage, and its association with Alzheimer's disease supports the involvement of immune and inflammatory pathways in the cause of the disease, rather than as a consequence of the disease. TREM2 variants associated with Alzheimer's disease induce partial loss of function of the TREM2 protein and alter the behaviour of microglial cells, including their response to amyloid plaques. TREM2 variants have also been shown to cause polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy and frontotemporal dementia. Although the low frequency of TREM2 variants makes it difficult to establish robust genotype-phenotype correlations, such studies are essential to enable a comprehensive understanding of the role of TREM2 in different neurological diseases, with the ultimate goal of developing novel therapeutic approaches.

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“…Interestingly, TREM2 and CD33 variants have been associated with PD [60–62] and the recycling of microglial TREM2 at the plasma membrane was suggested to be regulated by the vacuolar protein sorting 35 (VPS35) [63], which is associated with autosomal dominant PD [64]. However, the genetic data linking TREM2 with PD have not been replicated [65] and the involvement of TREM2 in PD still requires investigation.…”

Section: Introductionmentioning

confidence: 99%

Glial phagocytic clearance in Parkinson’s disease

Tremblay

Cookson

Civiero

2019

Mol Neurodegeneration

113

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An emerging picture suggests that glial cells’ loss of beneficial roles or gain of toxic functions can contribute to neurodegenerative conditions. Among glial cells, microglia and astrocytes have been shown to play phagocytic roles by engulfing synapses, apoptotic cells, cell debris, and released toxic proteins. As pathogenic protein accumulation is a key feature in Parkinson’s disease (PD), compromised phagocytic clearance might participate in PD pathogenesis. In contrast, enhanced, uncontrolled and potentially toxic glial clearance capacity could contribute to synaptic degeneration. Here, we summarize the current knowledge of the molecular mechanisms underlying microglial and astrocytic phagocytosis, focusing on the possible implication of phagocytic dysfunction in neuronal degeneration. Several endo-lysosomal proteins displaying genetic variants in PD are highly expressed by microglia and astrocytes. We also present the evidence that lysosomal defects can affect phagocytic clearance and discuss the therapeutic relevance of restoring or enhancing lysosomal function in PD.

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TREM2 rare variant p.R47H is not associated with Parkinson's disease

Cited by 17 publications

References 3 publications

TREM2 in Neurodegenerative Diseases

TREM2 in Neurodegenerative Diseases

The role of TREM2 in Alzheimer's disease and other neurodegenerative disorders

Glial phagocytic clearance in Parkinson’s disease

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