Hippocampal Pyk2 regulates specific social skills: Implications for schizophrenia.

Pyk2 has been shown previously to be involved in several psychological and cognitive alterations related to stress, Huntington's disease, and Alzheimer's disease. All these disorders are accompanied by different types of impairments in sociability, which has recently been linked to improper mitochondrial function. We hypothesize that Pyk2, which regulates mitochondria, could be associated with the regulation of mitochondrial dynamics and social skills. In the present manuscript, we report that a reduction of Pyk2 levels in mouse pyramidal neurons of the hippocampus decreased social dominance and aggressivity. Furthermore, social interactions induced robust Pyk2-dependent hippocampal changes in several oxidative phosphorylation complexes. We also observed that Pyk2 levels were increased in the CA1 pyramidal neurons of schizophrenic subjects, occurring alongside changes in different direct and indirect regulators of mitochondrial function including DISC1 and Grp75. Accordingly, overexpressing Pyk2 in hippocampal CA1 pyramidal cells mimicked some specific schizophrenia-like social behaviors in mice. In summary, our results indicate that Pyk2 might play a role in regulating specific social skills likely via mitochondrial dynamics and that there might be a link between Pyk2 levels in hippocampal neurons and social disturbances in schizophrenia.

Brain-gut photobiomodulation restores cognitive alterations in chronically stressed mice through the regulation of Sirt1 and neuroinflammation.

BACKGROUND: Chronic stress is an important risk factor for the development of major depressive disorder (MDD). Recent studies have shown microbiome dysbiosis as one of the pathogenic mechanisms associated with MDD. Thus, it is important to find novel non-pharmacological therapeutic strategies that can modulate gut microbiota and brain activity. One such strategy is photobiomodulation (PBM), which involves the non-invasive use of light. OBJECTIVE/HYPOTHESIS: Brain-gut PBM could have a synergistic beneficial effect on the alterations induced by chronic stress. METHODS: We employed the chronic unpredictable mild stress (CUMS) protocol to induce a depressive-like state in mice. Subsequently, we administered brain-gut PBM for 6 min per day over a period of 3 weeks. Following PBM treatment, we examined behavioral, structural, molecular, and cellular alterations induced by CUMS. RESULTS: We observed that the CUMS protocol induces profound behavioral alterations and an increase of sirtuin1 (Sirt1) levels in the hippocampus. We then combined the stress protocol with PBM and found that tissue-combined PBM was able to rescue cognitive alterations induced by CUMS. This rescue was accompanied by a restoration of hippocampal Sirt1 levels, prevention of spine density loss in the CA1 of the hippocampus, and the modulation of the gut microbiome. PBM was also effective in reducing neuroinflammation and modulating the morphology of Iba1-positive microglia. LIMITATIONS: The molecular mechanisms behind the beneficial effects of tissue-combined PBM are not fully understood. CONCLUSIONS: Our results suggest that non-invasive photobiomodulation of both the brain and the gut microbiome could be beneficial in the context of stress-induced MDD.

Thalamic Foxp2 regulates output connectivity and sensory-motor impairments in a model of Huntington's Disease.

BACKGROUND: Huntington's Disease (HD) is a disorder that affects body movements. Altered glutamatergic innervation of the striatum is a major hallmark of the disease. Approximately 30% of those glutamatergic inputs come from thalamic nuclei. Foxp2 is a transcription factor involved in cell differentiation and reported low in patients with HD. However, the role of the Foxp2 in the thalamus in HD remains unexplored. METHODS: We used two different mouse models of HD, the R6/1 and the HdhQ111 mice, to demonstrate a consistent thalamic Foxp2 reduction in the context of HD. We used in vivo electrophysiological recordings, microdialysis in behaving mice and rabies virus-based monosynaptic tracing to study thalamo-striatal and thalamo-cortical synaptic connectivity in R6/1 mice. Micro-structural synaptic plasticity was also evaluated in the striatum and cortex of R6/1 mice. We over-expressed Foxp2 in the thalamus of R6/1 mice or reduced Foxp2 in the thalamus of wild type mice to evaluate its role in sensory and motor skills deficiencies, as well as thalamo-striatal and thalamo-cortical connectivity in such mouse models. RESULTS: Here, we demonstrate in a HD mouse model a clear and early thalamo-striatal aberrant connectivity associated with a reduction of thalamic Foxp2 levels. Recovering thalamic Foxp2 levels in the mouse rescued motor coordination and sensory skills concomitant with an amelioration of neuropathological features and with a repair of the structural and functional connectivity through a restoration of neurotransmitter release. In addition, reduction of thalamic Foxp2 levels in wild type mice induced HD-like phenotypes. CONCLUSIONS: In conclusion, we show that a novel identified thalamic Foxp2 dysregulation alters basal ganglia circuits implicated in the pathophysiology of HD.

RTP801 mediates transneuronal toxicity in culture via extracellular vesicles.

Extracellular vesicles (EVs) play a crucial role in intercellular communication, participating in the paracrine trophic support or in the propagation of toxic molecules, including proteins. RTP801 is a stress-regulated protein, whose levels are elevated during neurodegeneration and induce neuron death. However, whether RTP801 toxicity is transferred trans-neuronally via EVs remains unknown. Hence, we overexpressed or silenced RTP801 protein in cultured cortical neurons, isolated their derived EVs (RTP801-EVs or shRTP801-EVs, respectively), and characterized EVs protein content by mass spectrometry (MS). RTP801-EVs toxicity was assessed by treating cultured neurons with these EVs and quantifying apoptotic neuron death and branching. We also tested shRTP801-EVs functionality in the pathologic in vitro model of 6-Hydroxydopamine (6-OHDA). Expression of RTP801 increased the number of EVs released by neurons. Moreover, RTP801 led to a distinct proteomic signature of neuron-derived EVs, containing more pro-apoptotic markers. Hence, we observed that RTP801-induced toxicity was transferred to neurons via EVs, activating apoptosis and impairing neuron morphology complexity. In contrast, shRTP801-EVs were able to increase the arborization in recipient neurons. The 6-OHDA neurotoxin elevated levels of RTP801 in EVs, and 6-OHDA-derived EVs lost the mTOR/Akt signalling activation via Akt and RPS6 downstream effectors. Interestingly, EVs derived from neurons where RTP801 was silenced prior to exposing them to 6-OHDA maintained Akt and RPS6 transactivation in recipient neurons. Taken together, these results suggest that RTP801-induced toxicity is transferred via EVs, and therefore, it could contribute to the progression of neurodegenerative diseases, in which RTP801 is involved.

Neuron-derived extracellular vesicles contain synaptic proteins, promote spine formation, activate TrkB-mediated signalling and preserve neuronal complexity.

Extracellular vesicles (EVs) play an important role in intercellular communication as carriers of signalling molecules such as bioactive miRNAs, proteins and lipids. EVs are key players in the functioning of the central nervous system (CNS) by influencing synaptic events and modulating recipient neurons. However, the specific role of neuron-to-neuron communication via EVs is still not well understood. Here, we provide evidence that primary neurons uptake neuron-derived EVs in the soma, dendrites, and even in the dendritic spines, and carry synaptic proteins. Neuron-derived EVs increased spine density and promoted the phosphorylation of Akt and ribosomal protein S6 (RPS6), via TrkB-signalling, without impairing the neuronal network activity. Strikingly, EVs exerted a trophic effect on challenged nutrient-deprived neurons. Altogether, our results place EVs in the spotlight for synaptic plasticity modulation as well as a possible therapeutic tool to fight neurodegeneration.

VPS13A knockdown impairs corticostriatal synaptic plasticity and locomotor behavior in a new mouse model of chorea-acanthocytosis.

Chorea-acanthocytosis (ChAc) is an inherited neurodegenerative movement disorder caused by VPS13A gene mutations leading to the absence of protein expression. The striatum is the most affected brain region in ChAc patients. However, the study of the VPS13A function in the brain has been poorly addressed. Here we generated a VPS13A knockdown (KD) model and aimed to elucidate the contribution of VPS13A to synaptic plasticity and neuronal communication in the corticostriatal circuit. First, we infected primary cortical neurons with miR30-shRNA against VPS13A and analyzed its effects on neuronal plasticity. VPS13A-KD neurons showed a higher degree of branching than controls, accompanied by decreased BDNF and PSD-95 levels, indicative of synaptic alterations. We then injected AAV-KD bilaterally in the frontal cortex and two different regions of the striatum of mice and analyzed the effects of VPS13A-KD on animal behavior and synaptic plasticity. VPS13A-KD mice showed modification of the locomotor behavior pattern, with increased exploratory behavior and hyperlocomotion. Corticostriatal dysfunction in VPS13A-KD mice was evidenced by impaired striatal long-term depression (LTD) after stimulation of cortical afferents, which was partially recovered by BDNF administration. VPS13A-KD did not lead to neuronal loss in the cortex or the striatum but induced a decrease in the neuronal release of CX3CL1 and triggered a microglial reaction, especially in the striatum. Notably, CX3CL1 administration partially restored the impaired corticostriatal LTD in VPS13A-KD mice. Our results unveil the involvement of VPS13A in neuronal connectivity modifying BDNF and CX3CL1 release. Moreover, the involvement of VPS13A in synaptic plasticity and motor behavior provides key information to further understand not only ChAc pathophysiology but also other neurological disorders.

Soluble mutant huntingtin drives early human pathogenesis in Huntington's disease.

Huntington's disease (HD) is an incurable inherited brain disorder characterised by massive degeneration of striatal neurons, which correlates with abnormal accumulation of misfolded mutant huntingtin (mHTT) protein. Research on HD has been hampered by the inability to study early dysfunction and progressive degeneration of human striatal neurons in vivo. To investigate human pathogenesis in a physiologically relevant context, we transplanted human pluripotent stem cell-derived neural progenitor cells (hNPCs) from control and HD patients into the striatum of new-born mice. Most hNPCs differentiated into striatal neurons that projected to their target areas and established synaptic connexions within the host basal ganglia circuitry. Remarkably, HD human striatal neurons first developed soluble forms of mHTT, which primarily targeted endoplasmic reticulum, mitochondria and nuclear membrane to cause structural alterations. Furthermore, HD human cells secreted extracellular vesicles containing mHTT monomers and oligomers, which were internalised by non-mutated mouse striatal neurons triggering cell death. We conclude that interaction of mHTT soluble forms with key cellular organelles initially drives disease progression in HD patients and their transmission through exosomes contributes to spread the disease in a non-cell autonomous manner.

M2 Cortex Circuitry and Sensory-Induced Behavioral Alterations in Huntington's Disease: Role of Superior Colliculus.

Early and progressive cortico-striatal circuit alterations have been widely characterized in Huntington's disease (HD) patients. Cortical premotor area, M2 cortex in rodents, is the most affected cortical input to the striatum from early stages in patients and is associated to the motor learning deficits present in HD mice. Yet, M2 cortex sends additional long-range axon collaterals to diverse output brain regions beyond basal ganglia. Here, we aimed to elucidate the contribution of M2 cortex projections to HD pathophysiology in mice. Using fMRI, M2 cortex showed most prominent functional connectivity alterations with the superior colliculus (SC) in symptomatic R6/1 HD male mice. Structural alterations were also detected by tractography, although diffusion weighted imaging measurements suggested preserved SC structure and similar electrophysiological responses were obtained in the SC on optogenetic stimulation of M2 cortical axons. Male and female HD mice showed behavioral alterations linked to SC function, including decreased defensive behavioral responses toward unexpected stimuli, such as a moving robo-beetle, and decreased locomotion on an unexpected flash of light. Additionally, GCamp6f fluorescence recordings with fiber photometry showed that M2 cortex activity was engaged by the presence of a randomly moving robo-bettle, an effect absent in HD male mice. Moreover, acute chemogenetic M2 cortex inhibition in WT mice shift behavioral responses toward an HD phenotype. Collectively, our findings highlight the involvement of M2 cortex activity in visual stimuli-induced behavioral responses, which are deeply altered in the R6/1 HD mouse model.SIGNIFICANCE STATEMENT Understanding brain circuit alterations in brain disorders is critical for developing circuit-based therapeutic interventions. The cortico-striatal circuit is the most prominently disturbed in Huntington's disease (HD); and particularly, M2 cortex has a prominent role. However, the same M2 cortical neurons send additional projections to several brain regions beyond striatum. We characterized new structural and functional circuitry alterations of M2 cortex in HD mouse models and found that M2 cortex projection to the superior colliculus (SC) was deeply impaired. Moreover, we describe differential responses to unexpected sensory stimulus in HD mouse models, which relies on SC function. Our data highlight the involvement of M2 cortex in SC-dependent sensory processing and its alterations in HD pathophysiology.

Cognitive and Emotional Symptoms Induced by Chronic Stress Are Regulated by EGR1 in a Subpopulation of Hippocampal Pyramidal Neurons.

Chronic stress is a core risk factor for developing a myriad of neurological disorders, including major depression. The chronicity of such stress can lead to adaptive responses or, on the contrary, to psychological maladaptation. The hippocampus is one of the most affected brain regions displaying functional changes in chronic stress. Egr1, a transcription factor involved in synaptic plasticity, is a key molecule regulating hippocampal function, but its role in stress-induced sequels has been poorly addressed. Emotional and cognitive symptoms were induced in mice by using the chronic unpredictable mild stress (CUMS) protocol. We used inducible double-mutant Egr1-CreERT2 x R26RCE mice to map the formation of Egr1-dependent activated cells. Results show that short- (2 days) or long-term (28 days) stress protocols in mice induce activation or deactivation, respectively, of hippocampal CA1 neural ensembles in an Egr1-activity-dependent fashion, together with an associated dendritic spine pathology. In-depth characterization of these neural ensembles revealed a deep-to-superficial switch in terms of Egr1-dependent activation of CA1 pyramidal neurons. To specifically manipulate deep and superficial pyramidal neurons of the hippocampus, we then used Chrna7-Cre (to express Cre in deep neurons) and Calb1-Cre mice (to express Cre in superficial neurons). We found that specific manipulation of superficial but not deep pyramidal neurons of the CA1 resulted in the amelioration of depressive-like behaviors and the restoration of cognitive impairments induced by chronic stress. In summary, Egr1 might be a core molecule driving the activation/deactivation of hippocampal neuronal subpopulations underlying stress-induced alterations involving emotional and cognitive sequels.

Ikzf1 as a novel regulator of microglial homeostasis in inflammation and neurodegeneration.

In the last two decades, microglia have emerged as key contributors to disease progression in many neurological disorders, not only by exerting their classical immunological functions but also as extremely dynamic cells with the ability to modulate synaptic and neural activity. This dynamic behavior, together with their heterogeneous roles and response to diverse perturbations in the brain parenchyma has raised the idea that microglia activation is more diverse than anticipated and that understanding the molecular mechanisms underlying microglial states is essential to unravel their role in health and disease from development to aging. The Ikzf1 (a.k.a. Ikaros) gene plays crucial roles in modulating the function and maturation of circulating monocytes and lymphocytes, but whether it regulates microglial functions and states is unknown. Using genetic tools, here we describe that Ikzf1 is specifically expressed in the adult microglia in brain regions such as cortex and hippocampus. By characterizing the Ikzf1 deficient mice, we observed that these mice displayed spatial learning deficits, impaired hippocampal CA3-CA1 long-term potentiation, and decreased spine density in pyramidal neurons of the CA1, which correlates with an increased expression of synaptic markers within microglia. Additionally, these Ikzf1 deficient microglia exhibited a severe abnormal morphology in the hippocampus, which is accompanied by astrogliosis, an aberrant composition of the inflammasome, and an altered expression of disease-associated microglia molecules. Interestingly, the lack of Ikzf1 induced changes on histone 3 acetylation and methylation levels in the hippocampus. Since the lack of Ikzf1 in mice appears to induce the internalization of synaptic markers within microglia, and severe gliosis we then analyzed hippocampal Ikzf1 levels in several models of neurological disorders. Ikzf1 levels were increased in the hippocampus of these neurological models, as well as in postmortem hippocampal samples from Alzheimer's disease patients. Finally, over-expressing Ikzf1 in cultured microglia made these cells hyporeactive upon treatment with lipopolysaccharide, and less phagocytic compared to control microglia. Altogether, these results suggest that altered Ikzf1 levels in the adult hippocampus are sufficient to induce synaptic plasticity and memory deficits via altering microglial state and function.

Meridianins Inhibit GSK3ß In Vivo and Improve Behavioral Alterations Induced by Chronic Stress.

Major depression disorder (MDD) is a severe mental alteration with a multifactorial origin, and chronic stress is one of the most relevant environmental risk factors associated with MDD. Although there exist some therapeutical options, 30% of patients are still resistant to any type of treatment. GSK3ß inhibitors are considered very promising therapeutic tools to counteract stress-related affectations. However, they are often associated with excessive off-target effects and undesired secondary alterations. Meridianins are alkaloids with an indole framework linked to an aminopyrimidine ring from Antarctic marine ascidians. Meridianins could overcome several of the aforementioned limitations since we previously demonstrated that they can inhibit GSK3ß activity without the associated neurotoxic or off-target effects in rodents. Here, we show that meridianins delivered into the lateral ventricle inhibited GSK3ß in several brain regions involved with stress-related symptoms. We also observed changes in major signaling pathways in the prefrontal cortex (Akt and PKA) and hippocampus (PKC and GluR1). Moreover, meridianins increased synaptic activity, specifically in the CA1 but not in the CA3 or other hippocampal subfields. Finally, we chronically treated the mice subjected to an unpredictable mild chronic stress (CUMS) paradigm with meridianins. Our results showed improvements produced by meridianins in behavioral alterations provoked by CUMS. In conclusion, meridianins could be of therapeutic interest to patients with stress-related disorders such as MDD.

Postnatal Foxp2 regulates early psychiatric-like phenotypes and associated molecular alterations in the R6/1 transgenic mouse model of Huntington's disease.

Huntington's Disease (HD) is a devastating disorder characterized by a triad of motor, psychiatric and cognitive manifestations. Psychiatric and emotional symptoms appear at early stages of the disease which are consistently described by patients and caregivers among the most disabling. Here, we show for the first time that Foxp2 is strongly associated with some psychiatric-like disturbances in the R6/1 mouse model of HD. First, 4-week-old (juvenile) R6/1 mice behavioral phenotype was characterized by an increased impulsive-like behavior and less aggressive-like behavior. In this line, we identified an early striatal downregulation of Foxp2 protein starting as soon as at postnatal day 15 that could explain such deficiencies. Interestingly, the rescue of striatal Foxp2 levels from postnatal stages completely reverted the impulsivity-phenotype and partially the social impairments concomitant with a rescue of dendritic spine pathology. A mass spectrometry study indicated that the rescue of spine loss was associated with an improvement of several altered proteins related with cytoskeleton dynamics. Finally, we reproduced and mimicked the impulsivity and social deficits in wild type mice by reducing their striatal Foxp2 expression from postnatal stages. Overall, these results imply that early postnatal reduction of Foxp2 might contribute to the appearance of some of the early psychiatric symptoms in HD.

Increased Phospho-AKT in Blood Cells from LRRK2 G2019S Mutation Carriers.

The purpose of this study was to investigate whether  differential phosphorylation states of blood markers can identify patients with LRRK2 Parkinson's disease (PD). We assessed phospho(P)-Ser-935-LRRK2 and P-Ser-473-AKT levels in peripheral blood cells from patients with G2019S LRRK2-associated PD (L2PD, n = 31), G2019S LRRK2 non-manifesting carriers (L2NMC, n = 26), idiopathic PD (iPD, n = 25), and controls (n = 40, total n = 122). We found no differences at P-Ser-935-LRRK2 between groups but detected a specific increase of P-Ser-473-AKT levels in all G2019S carriers, either L2PD or L2NMC, absent in iPD. Although insensitive to LRRK2 inhibition, our study identifies P-Ser-473-AKT as an endogenous candidate biomarker for peripheral inflammation in G2019S carriers using accessible blood cells. ANN NEUROL 2022;92:888-894.

Hippocampal Egr1-Dependent Neuronal Ensembles Negatively Regulate Motor Learning.

Motor skills learning is classically associated with brain regions including cerebral and cerebellar cortices and basal ganglia nuclei. Less is known about the role of the hippocampus in the acquisition and storage of motor skills. Here, we show that mice receiving a long-term training in the accelerating rotarod display marked hippocampal transcriptional changes and reduced pyramidal neurons activity in the CA1 region when compared with naive mice. Then, we use mice in which neural ensembles are permanently labeled in an Egr1 activity-dependent fashion. Using these mice, we identify a subpopulation of Egr1-expressing pyramidal neurons in CA1 activated in short-term (STT) and long-term (LTT) trained mice in the rotarod task. When Egr1 is downregulated in the CA1 or these neuronal ensembles are depleted, motor learning is improved whereas their chemogenetic stimulation impairs motor learning performance. Thus, Egr1 organizes specific CA1 neuronal ensembles during the accelerating rotarod task that limit motor learning. These evidences highlight the role of the hippocampus in the control of this type of learning and we provide a possible underlying mechanism.SIGNIFICANCE STATEMENT It is a major topic in neurosciences the deciphering of the specific circuits underlying memory systems during the encoding of new information. However, the potential role of the hippocampus in the control of motor learning and the underlying mechanisms has been poorly addressed. In the present work we show how the hippocampus responds to motor learning and how the Egr1 molecule is one of the major responsible for such phenomenon controlling the rate of motor coordination performances.

Meridianins Rescue Cognitive Deficits, Spine Density and Neuroinflammation in the 5xFAD Model of Alzheimer's Disease.

Glycogen synthase kinase 3ß (GSK3ß) is a core protein, with a relevant role in many neurodegenerative disorders including Alzheimer's disease. The enzyme has been largely studied as a potential therapeutic target for several neurological diseases. Unfortunately, preclinical and clinical studies with several GSK3ß inhibitors have failed due to many reasons such as excessive toxicity or lack of effects in human subjects. We previously reported that meridianins are potent GSK3ß inhibitors without altering neuronal viability. In the present work, we examine whether meridianins are capable to inhibit neural GSK3ß in vivo and if such inhibition induces improvements in the 5xFAD mouse model of Alzheimer's Disease. Direct administration of meridianins in the third ventricle of 5xFAD mice induced robust improvements of recognition memory and cognitive flexibility as well as a rescue of the synaptic loss and an amelioration of neuroinflammatory processes. In summary, our study points out meridianins as a potential compound to treat neurodegenerative disorders associated with an hyperactivation of GSK3ß such as Alzheimer's disease.

Pyk2 Regulates MAMs and Mitochondrial Dynamics in Hippocampal Neurons.

Pyk2 is a non-receptor tyrosine kinase enriched in hippocampal neurons, which can be activated by calcium-dependent mechanisms. In neurons, Pyk2 is mostly localised in the cytosol and dendritic shafts but can translocate to spines and/or to the nucleus. Here, we explore the function of a new localisation of Pyk2 in mitochondria-associated membranes (MAMs), a subdomain of ER-mitochondria surface that acts as a signalling hub in calcium regulation. To test the role of Pyk2 in MAMs' calcium transport, we used full Pyk2 knockout mice (Pyk2-/-) for in vivo and in vitro studies. Here we report that Pyk2-/- hippocampal neurons present increased ER-mitochondrial contacts along with defective calcium homeostasis. We also show how the absence of Pyk2 modulates mitochondrial dynamics and morphology. Taken all together, our results point out that Pyk2 could be highly relevant in the modulation of ER-mitochondria calcium efflux, affecting in turn mitochondrial function.

Unraveling the Spatiotemporal Distribution of VPS13A in the Mouse Brain.

Loss-of-function mutations in the human vacuolar protein sorting the 13 homolog A (VPS13A) gene cause Chorea-acanthocytosis (ChAc), with selective degeneration of the striatum as the main neuropathologic feature. Very little is known about the VPS13A expression in the brain. The main objective of this work was to assess, for the first time, the spatiotemporal distribution of VPS13A in the mouse brain. We found VPS13A expression present in neurons already in the embryonic stage, with stable levels until adulthood. VPS13A mRNA and protein distributions were similar in the adult mouse brain. We found a widespread VPS13A distribution, with the strongest expression profiles in the pons, hippocampus, and cerebellum. Interestingly, expression was weak in the basal ganglia. VPS13A staining was positive in glutamatergic, GABAergic, and cholinergic neurons, but rarely in glial cells. At the cellular level, VPS13A was mainly located in the soma and neurites, co-localizing with both the endoplasmic reticulum and mitochondria. However, it was not enriched in dendritic spines or the synaptosomal fraction of cortical neurons. In vivo pharmacological modulation of the glutamatergic, dopaminergic or cholinergic systems did not modulate VPS13A concentration in the hippocampus, cerebral cortex, or striatum. These results indicate that VPS13A has remarkable stability in neuronal cells. Understanding the distinct expression pattern of VPS13A can provide relevant information to unravel pathophysiological hallmarks of ChAc.

RTP801/REDD1 contributes to neuroinflammation severity and memory impairments in Alzheimer's disease.

RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death. Its downregulation in Parkinson's and Huntington's disease models ameliorates the pathological phenotypes. In the context of Alzheimer's disease (AD), the coding gene for RTP801, DDIT4, is responsive to Aß and modulates its cytotoxicity in vitro. Also, RTP801 mRNA levels are increased in AD patients' lymphocytes. However, the involvement of RTP801 in the pathophysiology of AD has not been yet tested. Here, we demonstrate that RTP801 levels are increased in postmortem hippocampal samples from AD patients. Interestingly, RTP801 protein levels correlated with both Braak and Thal stages of the disease and with GFAP expression. RTP801 levels are also upregulated in hippocampal synaptosomal fractions obtained from murine 5xFAD and rTg4510 mice models of the disease. A local RTP801 knockdown in the 5xFAD hippocampal neurons with shRNA-containing AAV particles ameliorates cognitive deficits in 7-month-old animals. Upon RTP801 silencing in the 5xFAD mice, no major changes were detected in hippocampal synaptic markers or spine density. Importantly, we found an unanticipated recovery of several gliosis hallmarks and inflammasome key proteins upon neuronal RTP801 downregulation in the 5xFAD mice. Altogether our results suggest that RTP801 could be a potential future target for theranostic studies since it could be a biomarker of neuroinflammation and neurotoxicity severity of the disease and, at the same time, a promising therapeutic target in the treatment of AD.

Proceedings of the Tenth International Meeting on Neuroacanthocytosis Syndromes.

The 10th International Meeting on Neuroacanthocytosis Syndromes was held online on March 10th12th, 2021. The COVID19 pandemic situation made our planned meeting in Barcelona on March 2020 to be suspended by one year, and finally took place online. The meeting followed the previous nine international symposia, the last of which was held in Dresden, Germany in March, 2018. The setting of the meeting encouraged interactions, exchange of ideas and networking opportunities among the high number of participants from around the globe, including scientists, neurologists and specially patients and caregivers. A total of 27 oral communications were distributed in 8 sessions with topics ranging from molecular and cellular functions of VPS13 genes and proteins, their involvement in Neuroacanthocytosis Syndromes and finally clinical aspects and patients care. In addition, 5 posters were presented. Altogether, scientists and neurologists discussed recent advances and set the bases for next steps, action points, and future studies in close collaboration with the patients associations, which are always actively involved in the whole process.