Marta Garcia-Miralles

• PhD
• Postdoctoral fellow at University of Freiburg

Environmental deprivation can have deleterious effects on adaptive myelination and oligodendroglia function. Early stage Huntington disease (HD) is characterised by white-matter myelin abnormalities in both humans and animal models. However, whether deprived environments exacerbate myelin-related pathological features of HD is not clearly understoo...

Background NPM1 is a phosphoprotein highly abundant in the nucleolus. However, additional nuclear functions have been attributed to NPM1, probably through interaction with other nuclear factors. DOT1L is one interaction partner of NPM1 that catalyzes methylation of histone H3 at lysine 79 (H3K79). DOT1L, playing functional roles in several biologic...

Transcriptional and proteomics analyses in human fragile X syndrome (FXS) neurons identified markedly reduced expression of COMT, a key enzyme involved in the metabolism of catecholamines, including dopamine, epinephrine and norepinephrine. FXS is the most common genetic cause of intellectual disability and autism spectrum disorders. COMT encodes f...

The cortical plate (CP) is composed of excitatory and inhibitory neurons, the latter of which originate in the ganglionic eminences. From their origin in the ventral telencephalon, maturing postmitotic interneurons migrate during embryonic development over some distance to reach their final destination in the CP. The histone methyltransferase Disru...

Cortical neurogenesis depends on the balance between self-renewal and differentiation of apical progenitors (APs). Here, we study the epigenetic control of AP's division mode by focusing on the enzymatic activity of the histone methyltransferase DOT1L. Combining lineage tracing with single-cell RNA sequencing of clonally related cells, we show at t...

Background The histone methyltransferase DOT1L catalyzes methylation of H3K79 and it is highly conserved in mammals. DOT1L plays a functional role in several biological processes including cell cycle regulation, DNA repair, RNA splicing and gene expression, suggesting a complex role in chromatin organization and regulation. Such a remarkable range...

The cortical plate is composed of excitatory and inhibitory neurons, the latter of which originate in the ganglionic eminences. From their origin in the ventral telencephalon, interneuron precursors migrate during embryonic development over some distance to reach their final destination in the cortical plate. The histone methyltransferase DOT1L is...

Ermin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here, we show that Ermin is essential for myelin sheath integrity and normal...

Background The contribution of grey matter (GM) and white matter (WM) degeneration to the progressive brain atrophy in Huntington Disease (HD) has been well studied. The pathology of the spinal cord in HD is comparatively less well documented. Aim Here we sought to investigate spinal cord pathology in a mouse model of HD, and in particular WM and...

Background: The relative contribution of grey matter (GM) and white matter (WM) degeneration to the progressive brain atrophy in Huntington's disease (HD) has been well studied. The pathology of the spinal cord in HD is comparatively less well documented. Objective: We aim to characterize spinal cord WM abnormalities in a mouse model of HD and e...

Ermin is an actin-binding protein found almost exclusively in the central nervous system (CNS) as a component of myelin sheaths. Although Ermin has been predicted to play a role in the formation and stability of myelin sheaths, this has not been directly examined in vivo. Here we show that Ermin is essential for myelin sheath integrity and normal s...

Olfactory dysfunction and altered neurogenesis are observed in several neurodegenerative disorders including Huntington disease (HD). These deficits occur early and correlate with a decline in global cognitive performance, depression and structural abnormalities of the olfactory system including the olfactory epithelium, bulb and cortices. However,...

Background Fragile X syndrome (FXS) is a neurodevelopmental disorder caused by epigenetic silencing of FMR1 and loss of FMRP expression. Efforts to understand the molecular underpinnings of the disease have been largely performed in rodent or non-isogenic settings. A detailed examination of the impact of FMRP loss on cellular processes and neuronal...

Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and ol...

Laquinimod, an immunomodulatory agent under clinical development for Huntington disease (HD), has recently been shown to confer behavioural improvements that are coupled with prevention of atrophy of the white matter (WM)-rich corpus callosum (CC) in the YAC128 HD mice. However, the nature of the WM improvements is not known yet. Here we investigat...

White matter abnormalities are a nearly universal pathological feature of neurodegenerative disorders including Huntington disease (HD). A long-held assumption is that this white matter pathology is simply a secondary outcome of the progressive neuronal loss that manifests with advancing disease. Using a mouse model of HD, here we show that white m...

Fragile X syndrome (FXS) is an incurable neurodevelopmental disorder with no effective treatment. FXS is caused by epigenetic silencing of FMR1 and loss of FMRP expression. To investigate the consequences of FMRP deficiency in the context of human physiology, we established isogenic FMR1 knockout (FMR1KO) human embryonic stem cells (hESCs). Integra...

Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and ol...

Background: Huntington Disease (HD) is an incurable autosomal dominant neurodegenerative disorder driven by an expansion repeat giving rise to the mutant huntingtin protein (mHtt), which is known to disrupt a multitude of transcriptional pathways. Pridopidine, a small molecule in development for treatment of HD, has been shown to improve motor sym...

Recent studies suggest that neurodegenerative diseases could affect brain structure and function in disease‐specific network patterns; however, how spontaneous activity affects structural covariance network (SC) is not clear. We hypothesized that hyper‐excitability in Huntington disease (HD) disrupts the coordinated structural and functional connec...

Structural and molecular myelination deficits represent early pathological features of Huntington disease (HD). Recent evidence from germ-free (GF) animals suggests a role for microbiota-gut-brain bidirectional communication in the regulation of myelination. In this study, we aimed to investigate the impact of microbiota on myelin plasticity and ol...

Results To evaluate successful learning, we tested for a linear increase in participants’ ability to enhance fMRI activity/connectivity voluntarily across visits. Participants in the SMA-activity NF group were the only group that showed a linear increase across visits. We also evaluated participants’ capacity to upregulate their brain activity afte...

Pridopidine is currently under clinical development for Huntington disease (HD), with on-going studies to better characterize its therapeutic benefit and mode of action. Pridopidine was administered either prior to the appearance of disease phenotypes or in advanced stages of disease in the YAC128 mouse model of HD. In the early treatment cohort, a...

Tissue macrophages arise during embryogenesis from yolk-sac (YS) progenitors that give rise to primitive YS macrophages. Until recently, it has been impossible to isolate or derive sufficient numbers of YS-derived macrophages for further study, but data now suggest that induced pluripotent stem cells (iPSCs) can be driven to undergo a process remin...

Obesity develops when caloric intake exceeds metabolic needs. Promoting energy expenditure represents an attractive approach in the prevention of this fast-spreading epidemic. Here, we report a novel pharmacological strategy in which a natural compound, narciclasine (ncls), attenuates diet-induced obesity (DIO) in mice by promoting energy expenditu...

Ncls does not affect food intake and fecal energy output in mice. (A) Cumulative food intake of HFD and NCD mice over a 48-h period after 6 wk of ncls or veh administration. (B) Average daily food intake of the mice described in (A). (C) Absolute daily caloric intake of the mice described in (A). (D) Feces production, (E) fecal energy content as de...

Effects of ncls treatment on mouse behavior. Mouse anxiety was evaluated by behavior tests including the (A) limb clasping test, (B) open field test, and (C) elevated plus maze test. Representative mouse trajectories for HFD-veh and HFD-ncls mice in the open field test were shown in panel (B). Values represent means ± SEM. Underlying data and metho...

Ncls promotes fatty acid metabolism in HFD mice. (A) Carbon dioxide production (VCO2) of HFD and NCD mice after 6 wk of ncls or veh administration. (B) RER of the mice described in (A). Ncls treatment significantly reduced the RER in HFD mice, indicating increased fatty acid metabolism in HFD-ncls mice. **** p < 0.0001. Underlying data and method o...

Correlation of skeletal muscle RNA-seq datasets between NCD-veh and NCD-ncls mice. The transcriptomic profiles of skeletal muscle of NCD-veh and NCD-ncls mice showed very high positive correlation (Pearson correlation coefficients, R = 0.999), suggesting ncls treatment did not lead to major transcriptional changes in NCD mice at the genomic level....

Effects of ncls treatment on the fat mass and lean mass in HFD and NCD mice. (A) Percentages of fat mass in total body weight of the ncls- or veh-treated mice on either an HFD or an NCD over a 9-wk period. (B) Percentages of fat mass and lean mass in total body weight of the mice after 6 wk of ncls or veh treatment (Week 8). * p < 0.05, ** p < 0.01...

Ncls partially activates AMPK signaling in C2C12 myotubes without PA treatment but exerts no detectable effects on AMPK signaling in the skeletal muscle of NCD mice. (A) Ncls treatment led to slight increases in pAMPKα and pACC2 in C2C12 myotubes without PA treatment. Western blots of total AMPKα and ACC2 were used for loading controls and subseque...

Effects of ncls on muscle strength and muscle mass. (A) Grip strength performance of mice at the beginning of the study (Baseline) and after 7 wk of ncls or veh treatment (Week 7). (B-F) Mass of (B) EDL, (C) soleus, (D) TA, (E) Gastr., and (F) quadricep muscles from mice treated for 7 wk with ncls or veh on either an HFD or an NCD. * p < 0.05, ** p...

Effects of ncls on muscle fiber area and fiber type in quadriceps of NCD and HFD mice. (A) Quadricep muscles were harvested from mice treated with ncls or veh on either an HFD or an NCD. Muscle sections were H&E stained, and the CSA of muscle fibers were quantified using ImageJ. (B) Muscle fiber type transition in the quadriceps upon ncls treatment...

Ncls promotes the expression of oxidative metabolism genes but represses glycolytic and fatty acid synthesis genes in quadriceps muscle of HFD mice. (A) The top 3 highly enriched categories of DEGs (>1.4-fold change) in quadricep muscles from HFD-ncls, NCD-veh and HFD-veh mice. (B) Expression patterns of representative genes from the “metabolic pro...

List of the 258 DEGs in the skeletal muscle of HFD-veh, NCD-veh, and HFD-ncls mice (>2-fold change). (XLSX)

Supporting materials and methods. (DOCX)

Contains underlying data for Figs 1A–1C,1E, 1H; 2B–2I; 3B, 3D–3F, 3H; 4D–4E; 5A, 5C–5I, 5K; 6A, 6B, 6E–6J; 7A, 7B, 7G and 8A–8D; S1A, S1B; S2A,S2B; S3A–S3F; S4B,S4C; S5; S6A–S6F; S7A,S7B; S8A; S9A–S9D; S10A–S10F and S11A Figs. (XLSX)

Ncls slightly enhances mitochondrial respiration in both murine myotubes and primary human myotubes in the absence of PA treatment. Relative mRNA expression of selected metabolic genes in (A) murine myotubes (C2C12) and (B) primary human myotubes (36C15Q) after treatment with or without 20 nM ncls for 48 h. The values of the untreated myotubes were...

Primers for qRT-PCR. (DOCX)

Effects of ncls on metabolic gene expression in WAT, BAT, liver, and heart. Relative mRNA expression of metabolic genes in (A) WAT, (B) BAT, (C), liver and (D) heart from mice treated with ncls or veh on either an HFD or an NCD. Underlying data and method of statistical analysis are provided in S1 Data. (TIF)

Expression levels of the genes described in S2 Table from the RNA-seq analysis. (DOCX)

Gene list of the enriched “Muscle protein” category in the up-regulated genes in the skeletal muscle of HFD-ncls mice (>2-fold change). (DOCX)

Pridopidine is currently in clinical development for Huntington’s disease (HD) and investigations to increase the understanding of its therapeutic benefit and mode of action are undergoing. In this study, we aim to investigate the efficacy and mechanism of action of pridopidine using the transgenic YAC128 mouse model of HD. Pridopidine was administ...

Background Olfactory dysfunction and altered neurogenesis are observed in several neurodegenerative disorders including Huntington’s disease (HD). These deficits are an early symptom and correlate with decline in cognitive performance, depression and degeneration of olfactory regions in the brain. Aims Despite clear evidence demonstrating olfactor...

Background Increasing evidence supports a role for abnormal immune activation and inflammatory responses in Huntington’s disease (HD). Aim and method In this study, we evaluated the therapeutic potential of laquinimod (1 and 10 mg/kg), a novel immunomodulatory agent shown to be protective in a number of neuroinflammatory conditions, in the YAC128...

Increasing evidence supports a role for abnormal immune activation and inflammatory responses in Huntington disease (HD). In this study, we evaluated the therapeutic potential of laquinimod (1 and 10 mg/kg), a novel immunomodulatory agent shown to be protective in a number of neuroinflammatory conditions, in the YAC128 mouse model of HD. Treatment...

Abnormal monoamine oxidase A and B (MAO-A/B) activity and an imbalance in monoamine neurotransmitters have been suggested to underlie the pathobiology of depression, a major psychiatric symptom observed in patients with neurodegenerative diseases, such as Huntington disease (HD). Increased MAO-A/B activity has been observed in brain tissue from pat...

Mutations within the LRRK2 gene have been identified in Parkinson's disease (PD) patients and have been implicated in the dysfunction of several cellular pathways. Here, we explore how pathogenic mutations and the inhibition of LRRK2 kinase activity affect cytoskeleton dynamics in mouse and human cell systems. We generated and characterized a novel...

Olfactory dysfunction and altered neurogenesis are observed in several neurodegenerative disorders including Huntington disease (HD). These deficits are an early symptom and correlate with decline in global cognitive performance, depression and degeneration of olfactory regions in the brain. The olfactory dysfunction observed in neurodegenerative d...

Quantification of the LRRK2 Interaction (WT and mutations) with ARHGEF7. Pixel densities of three independent experiments of interaction analyses between LRRK2 with mutations and ARHGEF7 (Figure 4) were calculated in relation to interaction between LRRK2 (45) and ARHGEF7. (0.16 MB TIF)

Pedigree of a family with Parkinson's disease. The new potentially pathogenic mutation N1437S is segregating with disease. (0.10 MB TIF)

Specificity control for used immunoprecipitation approach: endogenously expressed LRRK2 shows interaction with Tubulin but not with the GEF SOS1. Endogenous LRRK2 coupled on ProteinG agarose beads is not able to pull down the GEF SOS1 from mouse brain lysate, and the coupling of endogenous SOS1 shows no interaction to endogenous LRRK2 (A). The prev...

Specificity of the LRRK2 antibody. Specificity of the human-specific anti-LRRK2 antibody, used for immunofluorescence analysis, is shown by RNAi mediated knockdown of LRRK2 (siLRRK2-1) in SH-SY5Y cells in comparison to control siRNA transfected cells. (0.18 MB TIF)

Quantification of LRRK2 binding to GTP influenced by ARHGEF7. Pixel densities of three independent experiments of GTP-binding of mutated or WT LRRK2 in presence of ARHGEF7 (Figure 5) were calculated in relation to the GTP-binding of mutated or WT LRRK2 in presence of empty V5-vector. (0.17 MB TIF)

Mutations within the leucine-rich repeat kinase 2 (LRRK2) gene are a common cause of familial and sporadic Parkinson's disease. The multidomain protein LRRK2 exhibits overall low GTPase and kinase activity in vitro. Here, we show that the rho guanine nucleotide exchange factor ARHGEF7 and the small GTPase CDC42 are interacting with LRRK2 in vitro a...