Laboratory for Research on Neurodegenerative Disorders

Pavia, Italy

Laboratory for Research on Neurodegenerative Disorders

Pavia, Italy

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Brambilla L.,Laboratory for Research on Neurodegenerative Disorders | Guidotti G.,Laboratory for Research on Neurodegenerative Disorders | Martorana F.,Laboratory for Research on Neurodegenerative Disorders | Iyer A.M.,University of Amsterdam | And 3 more authors.
Human Molecular Genetics | Year: 2016

Considerable evidence indicates that neurodegeneration in amyotrophic lateral sclerosis (ALS) can be conditioned by a deleterious interplay between motor neurons and astrocytes. Astrocytes are the major glial component in the central nervous system (CNS) and fulfill several activities that are essential to preserve CNS homeostasis. In physiological and pathological conditions, astrocytes secrete a wide range of factors by which they exert multimodal influences on their cellular neighbours. Among others, astrocytes can secrete glial cell line-derived neurotrophic factor (GDNF), one of the most potent protective agents for motor neurons. This suggests that the modulation of the endogenous mechanisms that control the production of astrocytic GDNF may have therapeutic implications in motor neuron diseases, particularly ALS. In this study, we identified TNF receptor 1 (TNFR1) signalling as a major promoter of GDNF synthesis/release from human and mouse spinal cord astrocytes in vitro and in vivo. To determine whether endogenously produced TNFα can also trigger the synthesis of GDNF in the nervous system, we then focused on SOD1G93A ALS transgenic mice, whose affected tissues spontaneously exhibit high levels of TNFα and its receptor 1 at the onset and symptomatic stage of the disease. In SOD1G93A spinal cords, we verified a strict correlation in the expression of the TNFα, TNFR1 and GDNF triad at different stages of disease progression. Yet, ablation of TNFR1 completely abolished GDNF rises in both SOD1G93A astrocytes and spinal cords, a condition that accelerated motor neuron degeneration and disease progression. Our data suggest that the astrocytic TNFR1-GDNF axis represents a novel target for therapeutic intervention in ALS. © The Author 2016.


Pansarasa O.,National Neurological Institute C Mondino | Rossi D.,Laboratory for Research on Neurodegenerative Disorders | Berardinelli A.,National Neurological Institute C Mondino | Cereda C.,National Neurological Institute C Mondino
Molecular Neurobiology | Year: 2014

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease characterized by degeneration of upper and lower motor neurons (MNs), generalized weakness and muscle atrophy. The "neurocentric" view of ALS assumes that the disease primarily affects motor neurons, while muscle alterations only represent a consequence, in the periphery, of motor neuron loss. However, this outlook was recently challenged by evidence suggesting that non-neural cells such as microglia, astrocytes, peripheral blood mononuclear cells (PBMCs) and skeletal muscle fibres participate in triggering motor neuron degeneration, and this stressed the concept that alterations in different cell types may act together to exacerbate the disease. In this review, we will summarize the most recent findings on the alterations of skeletal muscle fibres found in ALS, with particular attention to the relationship between mutant SOD1 and skeletal muscle. We will analyze changes in muscle function, in the expression of myogenic regulatory factors, and also mitochondrial dysfunction, SOD1 aggregation and proteasome activity. © 2013 Springer Science+Business Media.


Benedusi V.,University of Milan | Martorana F.,Laboratory for Research on Neurodegenerative Disorders | Brambilla L.,Laboratory for Research on Neurodegenerative Disorders | Maggi A.,University of Milan | Rossi D.,Laboratory for Research on Neurodegenerative Disorders
Journal of Biological Chemistry | Year: 2012

Recent evidence highlights the peroxisome proliferator-activated receptors (PPARs) as critical neuroprotective factors in several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). To gain new mechanistic insights into the role of these receptors in the context of ALS, here we investigated how PPAR transcriptional activity varies in hSOD1G93A ALS transgenic mice. We demonstrate that PPARγ-driven transcription selectively increases in the spinal cord of symptomatic hSOD1G93A mice. This phenomenon correlates with the upregulation of target genes, such as lipoprotein lipase and glutathione S-transferase α-2, which are implicated in scavenging lipid peroxidation by-products. Such events are associated with enhanced PPARγ immunoreactivity within motor neuronal nuclei. This observation, and the fact that PPARγ displays increased responsiveness in cultured hSOD1G93A motor neurons, points to a role for this receptor in neutralizing deleterious lipoperoxidation derivatives within the motor cells. Consistently, in both motor neuron-like cultures and animal models, we report that PPARγ is activated by lipid peroxidation end products, such as 4-hydroxynonenal, whose levels are elevated in the cerebrospinal fluid and spinal cord from ALS patients. We propose that the accumulation of critical concentrations of lipid peroxidation adducts during ALS progression leads to the activation of PPARγ in motor neurons. This in turn triggers self-protective mechanisms that involve the up-regulation of lipid detoxification enzymes, such as lipoprotein lipase and glutathione S-transferaseα-2. Our findings indicate that anticipating natural protective reactions by pharmacologically modulating PPARγ transcriptional activity may attenuate neurodegeneration by limiting the damage induced by lipid peroxidation derivatives. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.


Martorana F.,Laboratory for Research on Neurodegenerative Disorders | Brambilla L.,Laboratory for Research on Neurodegenerative Disorders | Valori C.F.,University of Milan | Valori C.F.,Institute of Neuropathology | And 6 more authors.
Human Molecular Genetics | Year: 2012

Collective evidence indicates that motor neuron degeneration in amyotrophic lateral sclerosis (ALS) is non-cell-autonomous and requires the interaction with the neighboring astrocytes. Recently, we reported that a subpopulation of spinal cord astrocytes degenerates in the microenvironment of motor neurons in the hSOD1 G93A mouse model of ALS. Mechanistic studies in vitro identified a role for the excitatory amino acid glutamate in the gliodegenerative process via the activation of its inositol 1,4,5-triphosphate (IP 3)-generating metabotropic receptor 5 (mGluR5). Since non-physiological formation of IP 3 can prompt IP 3 receptor (IP 3R)-mediated Ca 2+ release from the intracellular stores and trigger various forms of cell death, here we investigated the intracellular Ca 2+ signaling that occurs downstream of mGluR5 in hSOD1 G93A-expressing astrocytes. Contrary to wild-type cells, stimulation of mGluR5 causes aberrant and persistent elevations of intracellular Ca 2+ concentrations ([Ca 2+] i) in the absence of spontaneous oscillations. The interaction of IP 3Rs with the anti-apoptotic protein Bcl-X L was previously described to prevent cell death by modulating intracellular Ca 2+ signals. In mutant SOD1-expressing astrocytes, we found that the sole BH4 domain of Bcl-X L, fused to the protein transduction domain of the HIV-1 TAT protein (TAT-BH4), is sufficient to restore sustained Ca 2+ oscillations and cell death resistance. Furthermore, chronic treatment of hSOD1 G93A mice with the TAT-BH4 peptide reduces focal degeneration of astrocytes, slightly delays the onset of the disease and improves both motor performance and animal lifespan. Our results point at TAT-BH4 as a novel glioprotective agent with a therapeutic potential for ALS. © The Author 2011. Published by Oxford University Press. All rights reserved.


Rossi D.,Laboratory for Research on Neurodegenerative Disorders | Martorana F.,Laboratory for Research on Neurodegenerative Disorders | Brambilla L.,Laboratory for Research on Neurodegenerative Disorders
CNS Drugs | Year: 2011

The seminal discovery that glial cells, particularly astrocytes, can release a number of gliotransmitters that serve as signalling molecules for the cross-talk with neighbouring cellular populations has recently changed our perception of brain functioning, as well as our view of the pathogenesis of several disorders of the CNS. Since glutamate was one of the first gliotransmitters to be identified and characterized, we tackle the mechanisms that underlie its release from astrocytes, including the Ca2 signals underlying its efflux from astroglia, and we discuss the involvement of these events in a number of relevant physiological processes, from the modulatory control of neighbouring synapses to the regulation of blood supply to cerebral tissues. The relevance of these mechanisms strongly indicates that the contribution of glial cells and gliotransmission to the activities of the brain cannot be overlooked, and any study of CNS physiopathology needs to consider glial biology to have a comprehensive overview of brain function and dysfunction. Abnormalites in the signalling that controls the astrocytic release of glutamate are described in several experimental models of neurological disorders, for example, AIDS dementia complex, Alzheimers disease and cerebral ischaemia. While the modalities of glutamate release from astrocytes remain poorly understood, and this represents a major impediment to the definition of novel therapeutic strategies targeting this process at the molecular level, some key mediators deputed to the control of the glial release of this excitatory amino acid have been identified. Among these, we can mention, for instance, proinflammatory cytokines, such as tumour necrosis factor-α, and prostaglandins. Agents that are able to block the major steps of tumour necrosis factor-α and prostaglandin production andor signalling can be proposed as novel therapeutic targets for the treatment of these disorders. © 2011 Adis Data Information BV. All rights reserved.


Valori C.F.,German Center for Neurodegenerative Diseases | Brambilla L.,Laboratory for Research on Neurodegenerative Disorders | Martorana F.,Laboratory for Research on Neurodegenerative Disorders | Rossi D.,Laboratory for Research on Neurodegenerative Disorders
Cellular and Molecular Life Sciences | Year: 2014

Despite indisputable progress in the molecular and genetic aspects of amyotrophic lateral sclerosis (ALS), a mechanistic comprehension of the neurodegenerative processes typical of this disorder is still missing and no effective cures to halt the progression of this pathology have yet been developed. Therefore, it seems that a substantial improvement of the outcome of ALS treatments may depend on a better understanding of the molecular mechanisms underlying neuronal pathology and survival as well as on the establishment of novel etiological therapeutic strategies. Noteworthy, a convergence of recent data from multiple studies suggests that, in cellular and animal models of ALS, a complex pathological interplay subsists between motor neurons and their non-neuronal neighbours, particularly glial cells. These observations not only have drawn attention to the physiopathological changes glial cells undergo during ALS progression, but they have moved the focus of the investigations from intrinsic defects and weakening of motor neurons to glia-neuron interactions. In this review, we summarize the growing body of evidence supporting the concept that different glial populations are critically involved in the dreadful chain of events leading to motor neuron sufferance and death in various forms of ALS. The outlined observations strongly suggest that glial cells can be the targets for novel therapeutic interventions in ALS. © 2013 Springer Basel.


Martorana F.,Laboratory for Research on Neurodegenerative Disorders | Guidotti G.,Laboratory for Research on Neurodegenerative Disorders | Brambilla L.,Laboratory for Research on Neurodegenerative Disorders | Rossi D.,Laboratory for Research on Neurodegenerative Disorders
Neural Plasticity | Year: 2015

Several lines of evidence suggest that astrocytes play a key role in modulating the immune responses of the central nervous system (CNS) to infections, injuries, or pathologies. Yet, their contribution to these processes remains mostly elusive. Astroglia are endowed with a wide range of toll-like receptors (TLR) by which they can sense infectious agents as well as endogenous danger signals released by damaged cells. Here we demonstrate that the activation of astrocytic TLR4 by bacterial lipopolysaccharide (LPS) challenge can promote nuclear factor B (NF-B)-dependent induction of pro-inflammatory and stress response mediators, particularly Tumor Necrosis Factor α (TNFα), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). Since the steroid lactone Withaferin A was described to inhibit NF-B activity in different cell types, we next determined the impact of this natural compound towards the identified astrocytic signalling pathway. Innate immune activation was induced by stimulation of the LPS/TLR4 axis in spinal cord astrocytes. We provide evidence that both pre-treating and post-treating the cells with Withaferin A attenuate astrocytic NF-B activity as well as the consequent production of TNFα, COX-2, and iNOS induced by stimulation of the LPS/TLR4 pathway. This study suggests that Withaferin A may be an eligible candidate for the treatment of neuroinflammatory and stress conditions characterized by an important astrocytic input. © 2015 Francesca Martorana et al.


PubMed | University of Amsterdam, Laboratory for Research on Neurodegenerative Disorders and German Center for Neurodegenerative Diseases
Type: Journal Article | Journal: Human molecular genetics | Year: 2016

Considerable evidence indicates that neurodegeneration in amyotrophic lateral sclerosis (ALS) can be conditioned by a deleterious interplay between motor neurons and astrocytes. Astrocytes are the major glial component in the central nervous system (CNS) and fulfill several activities that are essential to preserve CNS homeostasis. In physiological and pathological conditions, astrocytes secrete a wide range of factors by which they exert multimodal influences on their cellular neighbours. Among others, astrocytes can secrete glial cell line-derived neurotrophic factor (GDNF), one of the most potent protective agents for motor neurons. This suggests that the modulation of the endogenous mechanisms that control the production of astrocytic GDNF may have therapeutic implications in motor neuron diseases, particularly ALS. In this study, we identified TNF receptor 1 (TNFR1) signalling as a major promoter of GDNF synthesis/release from human and mouse spinal cord astrocytes in vitro and in vivo To determine whether endogenously produced TNF can also trigger the synthesis of GDNF in the nervous system, we then focused on SOD1


PubMed | Laboratory for Research on Neurodegenerative Disorders
Type: | Journal: Neural plasticity | Year: 2015

Several lines of evidence suggest that astrocytes play a key role in modulating the immune responses of the central nervous system (CNS) to infections, injuries, or pathologies. Yet, their contribution to these processes remains mostly elusive. Astroglia are endowed with a wide range of toll-like receptors (TLR) by which they can sense infectious agents as well as endogenous danger signals released by damaged cells. Here we demonstrate that the activation of astrocytic TLR4 by bacterial lipopolysaccharide (LPS) challenge can promote nuclear factor B (NF-B)-dependent induction of pro-inflammatory and stress response mediators, particularly Tumor Necrosis Factor (TNF), cyclooxygenase 2 (COX-2), and inducible nitric oxide synthase (iNOS). Since the steroid lactone Withaferin A was described to inhibit NF-B activity in different cell types, we next determined the impact of this natural compound towards the identified astrocytic signalling pathway. Innate immune activation was induced by stimulation of the LPS/TLR4 axis in spinal cord astrocytes. We provide evidence that both pre-treating and post-treating the cells with Withaferin A attenuate astrocytic NF-B activity as well as the consequent production of TNF, COX-2, and iNOS induced by stimulation of the LPS/TLR4 pathway. This study suggests that Withaferin A may be an eligible candidate for the treatment of neuroinflammatory and stress conditions characterized by an important astrocytic input.


Brambilla L.,Laboratory for Research on Neurodegenerative Disorders | Martorana F.,Laboratory for Research on Neurodegenerative Disorders | Rossi D.,Laboratory for Research on Neurodegenerative Disorders
Prion | Year: 2013

Growing evidence indicates that astrocytes cannot be just considered as passive supportive cells deputed to preserve neuronal activity and survival, but rather they are involved in a striking number of active functions that are critical to the performance of the central nervous system (CNS). As a consequence, it is becoming more and more evident that the peculiar properties of these cells can actively contribute to the extraordinary functional complexity of the brain and spinal cord. This new perception of the functioning of the CNS opens up a wide range of new possibilities to interpret various physiological and pathological events, and moves the focus beyond the neuronal compartment toward astrocyte-neuron interactions. With this in mind, here we provide a synopsis of the activities astrocytes perform in normal conditions, and we try to discuss what goes wrong with these cells in specific pathological conditions, such as Alzheimer disease, prion diseases and amyotrophic lateral sclerosis. © 2012 Landes Bioscience. Do not distribute.

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