DSpace Collection:https://hdl.handle.net/10171/520532024-03-29T01:20:38Z2024-03-29T01:20:38ZMicroglia and astrocyte activation is region-dependent in the alfa-synuclein mouse model of Parkinson's diseasehttps://hdl.handle.net/10171/667112024-01-30T11:31:40Z2023-01-01T00:00:00ZTitle: Microglia and astrocyte activation is region-dependent in the alfa-synuclein mouse model of Parkinson's disease
Abstract: Inflammation is a common feature in neurodegenerative diseases that contributes to neuronal loss. Previously, we demonstrated that the basal inflammatory tone differed between brain regions and, consequently, the reaction generated to a pro-inflammatory stimulus was different. In this study, we assessed the innate immune reaction in the midbrain and in the striatum using an experimental model of Parkinson's disease. An adeno-associated virus serotype 9 expressing the α-synuclein and mCherry genes or the mCherry gene was administered into the substantia nigra. Myeloid cells (CD11b+ ) and astrocytes (ACSA2+ ) were purified from the midbrain and striatum for bulk RNA sequencing. In the parkinsonian midbrain, CD11b+ cells presented a unique anti-inflammatory transcriptomic profile that differed from degenerative microglia signatures described in experimental models for other neurodegenerative conditions. By contrast, striatal CD11b+ cells showed a pro-inflammatory state and were similar to disease-associated microglia. In the midbrain, a prominent increase of infiltrated monocytes/macrophages was observed and, together with microglia, participated actively in the phagocytosis of dopaminergic neuronal bodies. Although striatal microglia presented a phagocytic transcriptomic profile, morphology and cell density was preserved and no active phagocytosis was detected. Interestingly, astrocytes presented a pro-inflammatory fingerprint in the midbrain and a low number of differentially displayed transcripts in the striatum. During α-synuclein-dependent degeneration, microglia and astrocytes experience context-dependent activation states with a different contribution to the inflammatory reaction. Our results point towards the relevance of selecting appropriate cell targets to design neuroprotective strategies aimed to modulate the innate immune system during the active phase of dopaminergic degeneration.2023-01-01T00:00:00ZElevated synaptic vesicle release probability in synaptophysin/gyrin family quadruple knockoutshttps://hdl.handle.net/10171/629722022-03-03T02:03:49Z2019-01-01T00:00:00ZTitle: Elevated synaptic vesicle release probability in synaptophysin/gyrin family quadruple knockouts
Abstract: Synaptophysins 1 and 2 and synaptogyrins 1 and 3 constitute a major family of
synaptic vesicle membrane proteins. Unlike other widely expressed synaptic vesicle proteins such
as vSNAREs and synaptotagmins, the primary function has not been resolved. Here, we report
robust elevation in the probability of release of readily releasable vesicles with both high and low
release probabilities at a variety of synapse types from knockout mice missing all four family
members. Neither the number of readily releasable vesicles, nor the timing of recruitment to the
readily releasable pool was affected. The results suggest that family members serve as negative
regulators of neurotransmission, acting directly at the level of exocytosis to dampen connection
strength selectively when presynaptic action potentials fire at low frequency. The widespread
expression suggests that chemical synapses may play a frequency filtering role in biological
computation that is more elemental than presently envisioned.2019-01-01T00:00:00ZMolecular and Cellular Mechanisms of Delayed Fracture Healing in Mmp10 (Stromelysin 2) Knockout Micehttps://hdl.handle.net/10171/626892024-01-24T09:29:38Z2021-01-01T00:00:00ZTitle: Molecular and Cellular Mechanisms of Delayed Fracture Healing in Mmp10 (Stromelysin 2) Knockout Mice
Abstract: The remodeling of the extracellular matrix is a central function in endochondral ossification and bone homeostasis. During secondary fracture healing, vascular invasion and bone growth requires the removal of the cartilage intermediate and the coordinate action of the collagenase matrix metalloproteinase (MMP)-13, produced by hypertrophic chondrocytes, and the gelatinase MMP-9, produced by cells of hematopoietic lineage. Interfering with these MMP activities results in impaired fracture healing characterized by cartilage accumulation and delayed vascularization. MMP-10, Stromelysin 2, a matrix metalloproteinase with high homology to MMP-3 (Stromelysin 1), presents a wide range of putative substrates identified in vitro, but its targets and functions in vivo and especially during fracture healing and bone homeostasis are not well defined. Here, we investigated the role of MMP-10 through bone regeneration in C57BL/6 mice. During secondary fracture healing, MMP-10 is expressed by hematopoietic cells and its maximum expression peak is associated with cartilage resorption at 14 days post fracture (dpf). In accordance with this expression pattern, when Mmp10 is globally silenced, we observed an impaired fracture-healing phenotype at 14 dpf, characterized by delayed cartilage resorption and TRAP-positive cell accumulation. This phenotype can be rescued by a non-competitive transplant of wild-type bone marrow, indicating that MMP-10 functions are required only in cells of hematopoietic linage. In addition, we found that this phenotype is a consequence of reduced gelatinase activity and the lack of proMMP-9 processing in macrophages. Our data provide evidence of the in vivo function of MMP-10 during endochondral ossification and defines the macrophages as the lead cell population in cartilage removal and vascular invasion2021-01-01T00:00:00ZHDAC inhibitors in acute myeloid leukemiahttps://hdl.handle.net/10171/623752024-01-24T09:29:38Z2019-01-01T00:00:00ZTitle: HDAC inhibitors in acute myeloid leukemia
Abstract: Acute myeloid leukemia (AML) is a hematological malignancy characterized by uncontrolled
proliferation, differentiation arrest, and accumulation of immature myeloid progenitors. Although
clinical advances in AML have been made, especially in young patients, long-term disease-free
survival remains poor, making this disease an unmet therapeutic challenge. Epigenetic alterations
and mutations in epigenetic regulators contribute to the pathogenesis of AML, supporting the
rationale for the use of epigenetic drugs in patients with AML. While hypomethylating agents have
already been approved in AML, the use of other epigenetic inhibitors, such as histone deacetylases
(HDAC) inhibitors (HDACi), is under clinical development. HDACi such as Panobinostat, Vorinostat,
and Tricostatin A have been shown to promote cell death, autophagy, apoptosis, or growth arrest in
preclinical AML models, yet these inhibitors do not seem to be effective as monotherapies, but rather
in combination with other drugs. In this review, we discuss the rationale for the use of different
HDACi in patients with AML, the results of preclinical studies, and the results obtained in clinical
trials. Although so far the results with HDACi in clinical trials in AML have been modest, there are
some encouraging data from treatment with the HDACi Pracinostat in combination with DNA
demethylating agents.2019-01-01T00:00:00Z