Maria Dolores Ledesma

Dr. Maria Dolores Ledesma


Research Focus & Metrics

Academic Career Length

13Years (2014-Present)

(Calculated once Scilit publication data is synced: current year − year of first publication + 1)

Representative Publications

View All Publications
31 January 2014 in Cell Death & Differentiation
Verified
Journal Article
Closed access
EREnrique Gabandé Rodríguez
Enrique Gabandé Rodríguez
Patricia BoyaPatricia Boya
Patricia Boya
VLV Labrador
V Labrador
CDC G Dotti
C G Dotti
MLMaria Dolores Ledesma
Maria Dolores Ledesma

7 December 2018 in The EMBO Journal
Verified
Journal Article
Open access
PDF file
EREnrique Gabandé Rodríguez
Enrique Gabandé Rodríguez
APAzucena Pérez‐Cañamás
Azucena Pérez‐Cañamás
BSBeatriz Soto‐Huelin
Beatriz Soto‐Huelin
DMDaniel N Mitroi
Daniel N Mitroi
SSSara Sánchez‐Redondo
Sara Sánchez‐Redondo
MLMaria Dolores Ledesma
Maria Dolores Ledesma
Neuropathic lysosomal storage disorders (LSDs) present with activated pro‐inflammatory microglia. However, anti‐inflammatory treatment failed to improve disease pathology. We characterise the mechanisms underlying microglia activation in Niemann–Pick disease type A (NPA). We establish that an NPA patient and the acid sphingomyelinase knockout (ASMko) mouse model show amoeboid microglia in neurodegeneration‐prone areas. In vivo microglia ablation worsens disease progression in ASMko mice. We demonstrate the coexistence of different microglia phenotypes in ASMko brains that produce cytokines or counteract neuronal death by clearing myelin debris. Overloading microglial lysosomes through myelin debris accumulation and sphingomyelin build‐up induces lysosomal damage and cathepsin B extracellular release by lysosomal exocytosis. Inhibition of cathepsin B prevents neuronal death and behavioural anomalies in ASMko mice. Similar microglia phenotypes occur in a Niemann–Pick disease type C mouse model and patient. Our results show a protective function for microglia in LSDs and how this is corrupted by lipid lysosomal overload. Data indicate cathepsin B as a key molecule mediating neurodegeneration, opening research pathways for therapeutic targeting of LSDs and other demyelinating diseases.

18 September 2019 in EMBO Reports
Verified
Journal Article
Open access
PDF file
DMDaniel N Mitroi
Daniel N Mitroi
GPGuadalupe Pereyra‐Gómez
Guadalupe Pereyra‐Gómez
BSBeatriz Soto‐Huelin
Beatriz Soto‐Huelin
FSFernando Senovilla
Fernando Senovilla
TKToshihide Kobayashi
Toshihide Kobayashi
MLMaria Dolores Ledesma
Maria Dolores Ledesma
NPC is a neurodegenerative disorder characterized by cholesterol accumulation in endolysosomal compartments. It is caused by mutations in the gene encoding NPC1, an endolysosomal protein mediating intracellular cholesterol trafficking. Cognitive and psychiatric alterations are hallmarks in NPC patients pointing to synaptic defects. However, the role of NPC1 in synapses has not been explored. We show that NPC1 is present in the postsynaptic compartment and is locally translated during LTP. A mutation in a region of the NPC1 gene commonly altered in NPC patients reduces NPC1 levels at synapses due to enhanced NPC1 protein degradation. This leads to shorter postsynaptic densities, increased synaptic cholesterol and impaired LTP in NPC1 nmf164 mice with cognitive deficits. NPC1 mediates cholesterol mobilization and enables surface delivery of CYP46A1 and GluA1 receptors necessary for LTP, which is defective in NPC1 nmf164 mice. Pharmacological activation of CYP46A1 normalizes synaptic levels of cholesterol, LTP and cognitive abilities, and extends life span of NPC1 nmf164 mice. Our results unveil NPC1 as a regulator of cholesterol dynamics in synapses contributing to synaptic plasticity, and provide a potential therapeutic strategy for NPC patients.

8 August 2014 in Frontiers in Neuroanatomy
Verified
Journal Article
Open access
PDF file
CDCarlos G. Dotti
Carlos G. Dotti
JEJose Antonio Esteban
Jose Antonio Esteban
MLMaria Dolores Ledesma
Maria Dolores Ledesma
Dynamic changes in the structure and composition of the membrane protrusions forming dendritic spines underlie memory and learning processes. In recent years a great effort has been made to characterize in detail the protein machinery that controls spine plasticity. However, we know much less about the involvement of lipids, despite being major membrane components and structure determinants. Moreover, protein complexes that regulate spine plasticity depend on specific interactions with membrane lipids for proper function and accurate intracellular signalling. In this review we attempt to gather the far from complete information available on the lipid composition at dendritic spine membranes and on its dynamics. We pay particular attention to the influence that spine lipid dynamism has on glutamate receptors, which are key regulators of synaptic plasticity.

21 August 2019 in Science Translational Medicine
Verified
Journal Article
Closed access
PDF file
LSLluís Samaranch
Lluís Samaranch
APAzucena Pérez-Cañamás
Azucena Pérez-Cañamás
BSBeatriz Soto-Huelin
Beatriz Soto-Huelin
VSVivek Sudhakar
Vivek Sudhakar
JJJerónimo Jurado-Arjona
Jerónimo Jurado-Arjona
MLMaria Dolores Ledesma
Maria Dolores Ledesma
Gene therapy for Niemann-Pick type A disease is safe in nonhuman primates and has therapeutic effects in a mouse model.

21 January 2014 in EMBO Molecular Medicine
Verified
Journal Article
Open access
PDF file
AAAna I Arroyo
Ana I Arroyo
PCPaola G Camoletto
Paola G Camoletto
LMLaura Morando
Laura Morando
MSMarco Sassoè-Pognetto
Marco Sassoè-Pognetto
MGMaurizio Giustetto
Maurizio Giustetto
MLMaria Dolores Ledesma
Maria Dolores Ledesma
Understanding the role of lipids in synapses and the aberrant molecular mechanisms causing the cognitive deficits that characterize most lipidosis is necessary to develop therapies for these diseases. Here we describe sphingomyelin (SM) as a key modulator of the dendritic spine actin cytoskeleton. We show that increased SM levels in neurons of acid sphingomyelinase knock out mice (ASMko), which mimic Niemann Pick disease type A (NPA), result in reduced spine number and size and low levels of filamentous actin. Mechanistically, SM accumulation decreases the levels of metabotropic glutamate receptors type I (mGluR1/5) at the synaptic membrane impairing membrane attachment and activity of RhoA and its effectors ROCK and ProfilinIIa. Pharmacological enhancement of the neutral sphingomyelinase rescues the aberrant molecular and morphological phenotypes in vitro and in vivo and improves motor and memory deficits in ASMko mice. Altogether, these data demonstrate the influence of SM and its catabolic enzymes in dendritic spine physiology and contribute to our understanding of the cognitive deficits of NPA patients, opening new perspectives for therapeutic interventions.