Progranulin (PGRN, encoded by the GRN gene) plays a key role in the development, survival, function, and maintenance of neurons and microglia in the mammalian brain. It regulates lysosomal ...biogenesis, inflammation, repair, stress response, and aging. GRN loss-of-function mutations cause neuronal ceroid lipofuscinosis or frontotemporal dementia-GRN (FTD-GRN) in a gene dosage-dependent manner. Mutations that reduce PGRN levels increase the risk for developing Alzheimer’s disease, Parkinson’s disease, and limbic-predominant age-related transactivation response DNA-binding protein 43 encephalopathy, as well as exacerbate the progression of amyotrophic lateral sclerosis (ALS) and FTD caused by the hexanucleotide repeat expansion in the C9orf72 gene. Elevating and/or restoring PGRN levels is an attractive therapeutic strategy and is being investigated for neurodegenerative diseases through multiple mechanisms of action.
Progranulin (PGRN) is a secreted, immune regulatory protein produced by myeloid cells and some neurons that regulates lysosomal function, neuronal survival, and inflammation.GRN loss-of-function mutations cause neuronal ceroid lipofuscinosis and frontotemporal dementia-GRN (FTD-GRN) in a dosage-dependent manner.Mutations that reduce PGRN levels are also associated with higher risk for amyotrophic lateral sclerosis (ALS) and FTD caused by the hexanucleotide repeat expansion in the C9orf72 gene, Parkinson’s disease (PD), Alzheimer’s disease (AD), limbic-predominant age-related transactivation response DNA-binding protein 43 (TDP-43) encephalopathy, Gaucher disease, and autism.PGRN overexpression is protective in animal models for AD, PD, FTD, ALS, stroke, Gaucher disease, and arthritis.PGRN is being investigated as a therapeutic target for neurodegenerative diseases through multiple mechanisms of action.
TREM2 is a receptor for lipids expressed in microglia. The R47H variant of human TREM2 impairs ligand binding and increases Alzheimer's disease (AD) risk. In mouse models of amyloid β (Aβ) ...accumulation, defective TREM2 function affects microglial response to Aβ plaques, exacerbating tissue damage, whereas TREM2 overexpression attenuates pathology. Thus, AD may benefit from TREM2 activation. Here, we examined the impact of an anti-human TREM2 agonistic mAb, AL002c, in a mouse AD model expressing either the common variant (CV) or the R47H variant of TREM2. Single-cell RNA-seq of microglia after acute systemic administration of AL002c showed induction of proliferation in both CV- and R47H-transgenic mice. Prolonged administration of AL002c reduced filamentous plaques and neurite dystrophy, impacted behavior, and tempered microglial inflammatory response. We further showed that a variant of AL002c is safe and well tolerated in a first-in-human phase I clinical trial and engages TREM2 based on cerebrospinal fluid biomarkers. We conclude that AL002 is a promising candidate for AD therapy.
Recent human genetic studies have challenged long standing hypotheses about the chain of events in Alzheimer's disease (AD), as the identification of genetic risk factors in microglial genes supports ...a causative role for microglia in the disease. Parallel transcriptome and histology studies at the single-cell level revealed a rich palette of microglial states affected by disease status and genetic risk factors. Taken together, those findings support microglia dysfunction as a central mechanism in AD etiology and thus the therapeutic potential of modulating microglial activity for AD treatment. Here we review how human genetic studies discovered microglial AD risk genes, such as TREM2, CD33, MS4A and APOE, and how experimental studies are beginning to decipher the cellular functions of some of these genes. Our review also focuses on recent transcriptomic studies of human microglia from postmortem tissue to critically assess areas of similarity and dissimilarity between human and mouse models currently in use in order to better understand the biology of innate immunity in AD.
Understanding the tissue-specific genetic controls of protein levels is essential to uncover mechanisms of post-transcriptional gene regulation. In this study, we generated a genomic atlas of protein ...levels in three tissues relevant to neurological disorders (brain, cerebrospinal fluid and plasma) by profiling thousands of proteins from participants with and without Alzheimer's disease. We identified 274, 127 and 32 protein quantitative trait loci (pQTLs) for cerebrospinal fluid, plasma and brain, respectively. cis-pQTLs were more likely to be tissue shared, but trans-pQTLs tended to be tissue specific. Between 48.0% and 76.6% of pQTLs did not co-localize with expression, splicing, DNA methylation or histone acetylation QTLs. Using Mendelian randomization, we nominated proteins implicated in neurological diseases, including Alzheimer's disease, Parkinson's disease and stroke. This first multi-tissue study will be instrumental to map signals from genome-wide association studies onto functional genes, to discover pathways and to identify drug targets for neurological diseases.
Human proteins are widely used as drug targets. Integration of large-scale protein-level genome-wide association studies (GWAS) and disease-related GWAS has thus connected genetic variation to ...disease mechanisms via protein. Previous proteome-by-phenome-wide Mendelian randomization (MR) studies have been mainly focused on plasma proteomes. Previous MR studies using the brain proteome only reported protein effects on a set of pre-selected tissue-specific diseases. No studies, however, have used high-throughput proteomics from multiple tissues to perform MR on hundreds of phenotypes.
Here, we performed MR and colocalization analysis using multi-tissue (cerebrospinal fluid (CSF), plasma, and brain from pre- and post-meta-analysis of several disease-focus cohorts including Alzheimer disease (AD)) protein quantitative trait loci (pQTLs) as instrumental variables to infer protein effects on 211 phenotypes, covering seven broad categories: biological traits, blood traits, cancer types, neurological diseases, other diseases, personality traits, and other risk factors. We first implemented these analyses with cis pQTLs, as cis pQTLs are known for being less prone to horizontal pleiotropy. Next, we included both cis and trans conditionally independent pQTLs that passed the genome-wide significance threshold keeping only variants associated with fewer than five proteins to minimize pleiotropic effects. We compared the tissue-specific protein effects on phenotypes across different categories. Finally, we integrated the MR-prioritized proteins with the druggable genome to identify new potential targets.
In the MR and colocalization analysis including study-wide significant cis pQTLs as instrumental variables, we identified 33 CSF, 13 plasma, and five brain proteins to be putative causal for 37, 18, and eight phenotypes, respectively. After expanding the instrumental variables by including genome-wide significant cis and trans pQTLs, we identified a total of 58 CSF, 32 plasma, and nine brain proteins associated with 58, 44, and 16 phenotypes, respectively. For those protein-phenotype associations that were found in more than one tissue, the directions of the associations for 13 (87%) pairs were consistent across tissues. As we were unable to use methods correcting for horizontal pleiotropy given most of the proteins were only associated with one valid instrumental variable after clumping, we found that the observations of protein-phenotype associations were consistent with a causal role or horizontal pleiotropy. Between 66.7 and 86.3% of the disease-causing proteins overlapped with the druggable genome. Finally, between one and three proteins, depending on the tissue, were connected with at least one drug compound for one phenotype from both DrugBank and ChEMBL databases.
Integrating multi-tissue pQTLs with MR and the druggable genome may open doors to pinpoint novel interventions for complex traits with no effective treatments, such as ovarian and lung cancers.
Human age-associated traits, such as cognitive decline, can be highly variable across the population, with some individuals exhibiting traits that are not expected at a given chronological age. Here ...we present differential aging (Δ-aging), an unbiased method that quantifies individual variability in age-associated phenotypes within a tissue of interest, and apply this approach to the analysis of existing transcriptome-wide cerebral cortex gene expression data from several cohorts totaling 1,904 autopsied human brain samples. We subsequently performed a genome-wide association study and identified the TMEM106B and GRN gene loci, previously associated with frontotemporal dementia, as determinants of Δ-aging in the cerebral cortex with genome-wide significance. TMEM106B risk variants are associated with inflammation, neuronal loss, and cognitive deficits, even in the absence of known brain disease, and their impact is highly selective for the frontal cerebral cortex of older individuals (>65 years). The methodological framework we describe can be broadly applied to the analysis of quantitative traits associated with aging or with other parameters.
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•Δ-Aging quantifies determinants of individuals appearing younger/older than peers•TMEM106B and GRN variants interact genetically in the regulation of Δ-aging•The role of TMEM106B in aging appears CNS region and life-stage selective•TMEM106B modulates CNS inflammatory and degenerative changes independently of disease
Rhinn et al. describe an integrative genomics approach to quantify aging rate in a tissue of interest. A subsequent GWAS analysis identifies the TMEM106B-progranulin genetic pathway as a key determinant of age-associated manifestations in the human cerebral cortex.
Alpha-synuclein is the main protein component of Lewy bodies, the pathological hallmark of Parkinson's disease. However, genetic modifiers of cerebrospinal fluid (CSF) alpha-synuclein levels remain ...unknown. The use of CSF levels of amyloid beta
, total tau, and phosphorylated tau
as quantitative traits in genetic studies have provided novel insights into Alzheimer's disease pathophysiology. A systematic study of the genomic architecture of CSF biomarkers in Parkinson's disease has not yet been conducted. Here, genome-wide association studies of CSF biomarker levels in a cohort of individuals with Parkinson's disease and controls (N = 1960) were performed. PD cases exhibited significantly lower CSF biomarker levels compared to controls. A SNP, proxy for APOE ε4, was associated with CSF amyloid beta
levels (effect = - 0.5, p = 9.2 × 10
). No genome-wide loci associated with CSF alpha-synuclein, total tau, or phosphorylated tau
levels were identified in PD cohorts. Polygenic risk score constructed using the latest Parkinson's disease risk meta-analysis were associated with Parkinson's disease status (p = 0.035) and the genomic architecture of CSF amyloid beta
(R
= 2.29%; p = 2.5 × 10
). Individuals with higher polygenic risk scores for PD risk presented with lower CSF amyloid beta
levels (p = 7.3 × 10
). Two-sample Mendelian Randomization revealed that CSF amyloid beta
plays a role in Parkinson's disease (p = 1.4 × 10
) and age at onset (p = 7.6 × 10
), an effect mainly mediated by variants in the APOE locus. In a subset of PD samples, the APOE ε4 allele was associated with significantly lower levels of CSF amyloid beta
(p = 3.8 × 10
), higher mean cortical binding potentials (p = 5.8 × 10
), and higher Braak amyloid beta score (p = 4.4 × 10
). Together these results from high-throughput and hypothesis-free approaches converge on a genetic link between Parkinson's disease, CSF amyloid beta
, and APOE.
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