DSpace Collection:
https://hdl.handle.net/10171/18143
2024-03-29T13:49:42ZPharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model
https://hdl.handle.net/10171/68822
Title: Pharmacological inhibition of the integrated stress response accelerates disease progression in an amyotrophic lateral sclerosis mouse model
Abstract: Background and purpose: The integrated stress response (ISR) regulates translation in response to diverse stresses. ISR activation has been documented in amyotrophic lateral sclerosis (ALS) patients and ALS experimental models. In experimental models, both ISR stimulation and inhibition prevented ALS neurodegeneration; however, which mode of ISR regulation would work in patients is still debated. We previously demonstrated that the ISR modulator ISRIB (Integrated Stress Response InhiBitor, an eIF2B activator) enhances survival of neurons expressing the ALS neurotoxic allele SOD1 G93A. Here, we tested the effect of two ISRIB-like eIF2B activators (2BAct and PRXS571) in the disease progression of transgenic SOD1G93A mice.
Experimental approach: After biochemical characterization in primary neurons, SOD1G93A mice were treated with 2BAct and PRXS571. Muscle denervation of vulnerable motor units was monitored with a longitudinal electromyographic test. We used a clinical score to document disease onset and progression; force loss was determined with the hanging wire motor test. Motor neuronal survival was assessed by immunohistochemistry.
Key results: In primary neurons, 2BAct and PRXS571 relieve the ISR-imposed translational inhibition while maintaining high ATF4 levels. Electromyographic recordings evidenced an earlier and more dramatic muscle denervation in treated SOD1G93A mice that correlated with a decrease in motor neuron survival. Both compounds anticipated disease onset and shortened survival time.
Conclusion and implications: 2BAct and PRXS571 anticipate disease onset, aggravating muscle denervation and motor neuronal death of SOD1G93A mice. This study reveals that the ISR works as a neuroprotective pathway in ALS motor neurons and reveals the toxicity that eIF2B activators may display in ALS patients.2023-01-01T00:00:00ZStriatal synaptic bioenergetic and autophagic decline in premotor experimental parkinsonism
https://hdl.handle.net/10171/66745
Title: Striatal synaptic bioenergetic and autophagic decline in premotor experimental parkinsonism
Abstract: Synaptic impairment might precede neuronal degeneration in Parkinson's disease. However, the intimate mechanisms altering synaptic function by the accumulation of presynaptic α-synuclein in striatal dopaminergic terminals before dopaminergic death occurs, have not been elucidated. Our aim is to unravel the sequence of synaptic functional and structural changes preceding symptomatic dopaminergic cell death. As such, we evaluated the temporal sequence of functional and structural changes at striatal synapses before parkinsonian motor features appear in a rat model of progressive dopaminergic death induced by overexpression of the human mutated A53T α-synuclein in the substantia nigra pars compacta, a protein transported to these synapses. Sequential window acquisition of all theoretical mass spectra proteomics identified deregulated proteins involved first in energy metabolism and later, in vesicle cycling and autophagy. After protein deregulation and when α-synuclein accumulated at striatal synapses, alterations to mitochondrial bioenergetics were observed using a Seahorse XF96 analyser. Sustained dysfunctional mitochondrial bioenergetics was followed by a decrease in the number of dopaminergic terminals, morphological and ultrastructural alterations, and an abnormal accumulation of autophagic/endocytic vesicles inside the remaining dopaminergic fibres was evident by electron microscopy. The total mitochondrial population remained unchanged whereas the number of ultrastructurally damaged mitochondria increases as the pathological process evolved. We also observed ultrastructural signs of plasticity within glutamatergic synapses before the expression of motor abnormalities, such as a reduction in axospinous synapses and an increase in perforated postsynaptic densities. Overall, we found that a synaptic energetic failure and accumulation of dysfunctional organelles occur sequentially at the dopaminergic terminals as the earliest events preceding structural changes and cell death. We also identify key proteins involved in these earliest functional abnormalities that may be modulated and serve as therapeutic targets to counterbalance the degeneration of dopaminergic cells to delay or prevent the development of Parkinson's disease.2022-01-01T00:00:00ZMicroglia and astrocyte activation is region-dependent in the alfa-synuclein mouse model of Parkinson's disease
https://hdl.handle.net/10171/66711
Title: 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.2023-01-01T00:00:00ZTerapia celular “neuro-restauradora” en la enfermedad de Parkinson: un debate pendiente
https://hdl.handle.net/10171/64629
Title: Terapia celular “neuro-restauradora” en la enfermedad de Parkinson: un debate pendiente
Abstract: Existe en la actualidad un gran entusiasmo sobre las perspectivas derivadas de la denominada terapia
celular en la enfermedad de Parkinson. Este entusiasmo ha sobrepasado la esfera de la comunidad médica,
llegando hasta el público general, y se ha venido alimentando de un considerable debate ético y político,
hurtándose en todo momento la necesidad de un análisis realmente científico sobre las cualidades y limitaciones reales del tratamiento con células madre en las enfermedades neurodegenerativas. La enfermedad de Parkinson con frecuencia se observa desde una perspectiva simplista, como una mera neurodegeneración de la vía dopaminérgica nigroestriada, punto de vista bajo el que se colocan diferentes diseños tendentes a reemplazar la falta de dopamina en el estriado, mediante el empleo de distintos tipos de terapia celular. En este sentido, es necesario señalar por un lado la naturaleza multisistémica y generalizada de la enfermedad, y por otro lado el carácter progresivo del proceso neurodegenerativo de la enfermedad de Parkinson. Bajo este enfoque, pretender que el mero reemplazo de la dopamina estriatal mediante terapia celular sustitutiva, pueda corregir el carácter generalizado y progresivo de la enfermedad es una aspiración quimérica, que únicamente contribuye a generar expectativas infundadas en el público general. Este artículo pretende argumentar desde un punto de vista puramente científico las dudas sobre las expectativas creadas con estos nuevos diseños terapéuticos.; At present there is great enthusiasm over the perspectives deriving from so-called cell therapy in
Parkinson’s disease. This enthusiasm has spread beyond the ambit of the medical community, reaching
the general public, and has been fuelled by a considerable ethical and political debate, sidestepping
the need for a really scientific analysis of the real qualities and limitations of treatment with stem-cells in
neurodegenerative diseases. Parkinson’s disease is frequently observed from a simplistic perspective, as a
mere neurodegeneration of the nigrostriatal dopaminergic pathway. This viewpoint encompasses
different designs that tend to replace the lack of dopamine in the striatum through the use of different
types of cell therapy. In this respect, it is important to indicate, on the one hand, the multisystemic and
generalised nature of the disease and, on the other, the progressive character of the neurodegenerative
process of Parkinson’s disease. With this approach, to claim that the mere replacement of striatal dopamine
through replacement cell therapy can correct the generalised and progressive character of the disease is
a fanciful aspiration, which can only contribute to generating unfounded expectations in the general
public. This article attempts to set out from a purely scientific point of view the doubts over the
expectations created by these new therapeutic designs.2004-01-01T00:00:00Z