Genome-Wide DNA Methylation in Early-Onset-Dementia Patients Brain Tissue and Lymphoblastoid Cell Lines

Epigenetics, a potential underlying pathogenic mechanism of neurodegenerative diseases, has been in the scope of several studies performed so far. However, there is a gap in regard to analyzing different forms of early-onset dementia and the use of Lymphoblastoid cell lines (LCLs). We performed a genome-wide DNA methylation analysis on sixty-four samples (from the prefrontal cortex and LCLs) including those taken from patients with early-onset forms of Alzheimer’s disease (AD) and frontotemporal dementia (FTD) and healthy controls. A beta regression model and adjusted p-values were used to obtain differentially methylated positions (DMPs) via pairwise comparisons. A correlation analysis of DMP levels with Clariom D array gene expression data from the same cohort was also performed. The results showed hypermethylation as the most frequent finding in both tissues studied in the patient groups. Biological significance analysis revealed common pathways altered in AD and FTD patients, affecting neuron development, metabolism, signal transduction, and immune system pathways. These alterations were also found in LCL samples, suggesting the epigenetic changes might not be limited to the central nervous system. In the brain, CpG methylation presented an inverse correlation with gene expression, while in LCLs, we observed mainly a positive correlation. This study enhances our understanding of the biological pathways that are associated with neurodegeneration, describes differential methylation patterns, and suggests LCLs are a potential cell model for studying neurodegenerative diseases in earlier clinical phases than brain tissue

Galectin-3 is upregulated in frontotemporal dementia patients with subtype specificity

INTRODUCTIONNeuroinflammation is a major contributor to the progression of frontotemporal dementia (FTD). Galectin-3 (Gal-3), a microglial activation regulator, holds promise as a therapeutic target and potential biomarker. Our study aimed to investigate Gal-3 levels in patients with FTD and assess its diagnostic potential.METHODSWe examined Gal-3 levels in brain, serum, and cerebrospinal fluid (CSF) samples of patients with FTD and controls. Multiple linear regressions between Gal-3 levels and other FTD markers were explored.RESULTSGal-3 levels were increased significantly in patients with FTD, mainly across brain tissue and CSF, compared to controls. Remarkably, Gal-3 levels were higher in cases with tau pathology than TAR-DNA Binding Protein 43 (TDP-43) pathology. Only MAPT mutation carriers displayed increased Gal-3 levels in CSF samples, which correlated with total tau and 14-3-3.DISCUSSIONOur findings underscore the potential of Gal-3 as a diagnostic marker for FTD, particularly in MAPT cases, and highlights the relation of Gal-3 with neuronal injury markers

Neuroprotective activity of ursodeoxycholic acid in CHMP2B Intron5 models of frontotemporal dementia

Frontotemporal dementia (FTD) is one of the most prevalent forms of early-onset dementia. It represents part of the FTD-Amyotrophic Lateral Sclerosis (ALS) spectrum, a continuum of genetically and pathologically overlapping disorders. FTD-causing mutations in CHMP2B, a gene encoding a core component of the heteromeric ESCRT-III Complex, lead to perturbed endosomal-lysosomal and autophagic trafficking with impaired proteostasis. While CHMP2B mutations are rare, dysfunctional endosomal-lysosomal signalling is common across the FTD-ALS spectrum. Using our established Drosophila and mammalian models of CHMP2BIntron5 induced FTD we demonstrate that the FDA-approved compound Ursodeoxycholic Acid (UDCA) conveys neuroprotection, downstream of endosomal-lysosomal dysfunction in both Drosophila and primary mammalian neurons. UDCA exhibited a dose dependent rescue of neuronal structure and function in Drosophila pan-neuronally expressing CHMP2BIntron5. Rescue of CHMP2BIntron5 dependent dendritic collapse and apoptosis with UDCA in rat primary neurons was also observed. UDCA failed to ameliorate aberrant accumulation of endosomal and autophagic organelles or ubiquitinated neuronal inclusions in both models. We demonstrate the neuroprotective activity of UDCA downstream of endosomal-lysosomal and autophagic dysfunction, delineating the molecular mode of action of UDCA and highlighting its potential as a therapeutic for the treatment of FTD-ALS spectrum disorders

RNA Dysregulation in an Endosomal Impaired Drosophila Model of Frontotemporal Dementia/Amyotrophic Lateral Sclerosis

Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS) are two overlapping neurodegenerative disorders characterised by the dysfunction and the death of neurons. They are considered two ends of a spectrum that share common pathological mechanisms. Different mutations in several human genes, involved in endosomal traffic and RNA regulation, can cause FTD, ALS or both. Mutations in charged multivesicular body protein 2B (CHMP2B), whose main known function is endolysosomal cargo trafficking and biogenesis of multivesicular bodies (MVB), can cause FTD and ALS. In this thesis, the mutation of interest is a G>C transition in the splice acceptor site of exon 6 resulting in a toxic variant, CHMP2BIntron5, where the C-terminal of the protein is truncated. This specific mutation causes a rare hereditary form of FTD, FTD-3. This work establishes a role for Drosophila CHMP2B (dCHMP2B) at the synapse, demonstrating a neuronal functional requirement. Pathologically, the majority of ALS cases have TDP-43 aggregation, whereas FTD cases have inclusions that are either tau or TDP-43 positive. FTD-3 has no apparent inclusions. Despite the lack of TDP-43 pathology, this thesis identifies a genetic interaction between CHMP2B and TDP-43, and interacting-TDP-43 pathways, in health and disease of the Drosophila nervous system. TDP-43 functions as an RNA regulatory protein that binds to small RNAs. In this investigation, two RNA regulatory pathways are identified as modifiers of the toxicity caused by CHMP2BIntron5 expression in our Drosophila model: retrotransposon/retrovirus (RT/RV) reactivation and nonsense-mediated decay (NMD) dysregulation. Taken together, these findings reinforce the idea that RNA dysregulation and endosomal dysfunction are two cellular mechanisms that converge under the pathology of FTD/ALS

Retrovirus reactivation in CHMP2BIntron5 models of frontotemporal dementia

Abstract Frontotemporal dementia (FTD) is the second most prevalent form of pre-senile dementia after Alzheimer’s disease. Amyotrophic lateral sclerosis (ALS) can overlap genetically, pathologically and clinically with FTD indicating the two conditions are ends of a spectrum and may share common pathological mechanisms. FTD–ALS causing mutations are known to be involved in endosomal trafficking and RNA regulation. Using an unbiased genome-wide genetic screen to identify mutations affecting an FTD–ALS-related phenotype in Drosophila caused by CHMP2BIntron5 expression, we have uncovered repressors of retrovirus (RV) activity as modifiers of CHMP2BIntron5 toxicity. We report that neuronal expression of CHMP2BIntron5 causes an increase in the activity of the endogenous Drosophila RV, gypsy, in the nervous system. Genetically blocking Drosophila gypsy activation and pharmacologically inhibiting viral reverse transcriptase activity prevents degenerative phenotypes observed in fly and rat neurons. These findings directly link endosomal dysfunction to RV de-repression in an FTD–ALS model without TDP-43 pathology. These observations may contribute an understanding to previous discoveries of RV activation in ALS affected patients.</jats:p