Neuronal Stress Response Research Articles

From adaption to death: endoplasmic reticulum stress as a novel target of selective neurodegeneration?

From adaption to death: endoplasmic reticulum stress as a novel target of selective neurodegeneration?

Involvement of endoplasmic reticulum stress response in orofacial inflammatory pain.

Endoplasmic reticulum (ER) stress is involved in many neurological diseases and inflammatory responses. Inflammatory mediators induce neuronal damage and trigger the neuropathic or inflammatory pain. But there is very little data on the role of the ER stress response in pain mechanisms. In this study, we explored whether the ER stress response is involved in orofacial inflammatory pain by using a complete Freund's adjuvant (CFA)-injected rat model. The thermal pain hypersensitivity increased significantly after CFA injection. We found that the protein and mRNA levels of ER stress response genes, GRP78/Bip and p-eIF2α, increased significantly in trigeminal ganglion (TG) of CFA-injected rats compared to control animals. In immunofluorescence analysis, a significant increase of GRP78 and p-eIF2α immunopositive neurons was observed in CFA-injected TG compared to control TG. When we administered an ER stress modulator, salubrinal, CFA-induced thermal pain hypersensitivity was temporally reduced. Thus, our study suggests that ER stress responses in TG neurons contribute to CFA-induced inflammatory pain, and may comprise an important molecular mechanism underlying the orofacial inflammatory pain pathway.

Role of the mitochondrial Ca2+ uniporter in Pb2+-induced oxidative stress in human neuroblastoma cells

Lead (Pb2+) has been shown to induce cellular oxidative stress, which is linked to changes in intracellular calcium (Ca2+) concentration. The mitochondrial Ca2+ uniporter (MCU) participates in the maintenance of Ca2+ homeostasis in neurons, but its role in Pb2+-induced oxidative stress is unclear. To address this question, oxidative stress was induced in human neuroblastoma SH-SY5Y cells and in newborn rats by Pb2+ treatment. The results showed that the production of reactive oxygen species is increased in cells upon treatment with Pb2+ in a dose-dependent manner, while glutathione and MCU expression were reduced. Moreover, neuronal nitric oxide synthase protein expression was elevated in rats exposed to Pb2+ during gestation, while MCU expression was decreased. Application of the MCU activator spermine or MCU overexpression reversed Pb2+-induced oxidative stress and inhibition of mitochondrial Ca2+ uptake, while the MCU inhibitor Ru360 and MCU knockdown potentiated the effects of Pb2+. These results indicate that the MCU mediates the Pb2+-induced oxidative stress response in neurons through the regulation of mitochondrial Ca2+ influx.

Autophagy-mediated stress response in motor neurons after hypothermic spinal cord ischemia in rabbits

The development of spinal cord injury is believed to be related to the vulnerability of spinal motor neurons to ischemia. However, the mechanisms underlying this vulnerability have not been fully investigated. Previously, we reported that spinal motor neurons are lost likely due to autophagy and that local hypothermia prevents such spinal motor neuron death. Therefore, we investigated the role of autophagy in normothermic and hypothermic spinal cord ischemia using an immunohistochemical analysis of Beclin 1 (BCLN1; B-cell leukemia 2 protein [Bcl-2] interacting protein), Bcl-2, and γ-aminobutyric acid type-A receptor-associated protein (GABARAP), which are considered autophagy-related proteins. We used rabbit normothermic and hypothermic transient spinal cord ischemia models using a balloon catheter. Neurologic function was assessed according to the Johnson score, and the spinal cord was removed at 8hours and 1, 2, and 7days after reperfusion, and morphologic changes were examined using hematoxylin and eosin staining. A Western blot analysis and histochemical study of BCLN1, Bcl-2, and GABARAP, and double-labeled fluorescent immunocytochemical studies were performed. There were significant differences in the physiologic function between the normothermic model and hypothermic model after the procedure (P< .05). In the normothermic model, most of the motor neurons were selectively lost at7days of reperfusion (P< .001 compared with the sham group), and they were preserved in the hypothermic model (P= .574 compared with the sham group). The Western blot analysis revealed that the sustained expression of the autophagy markers, BCLN1 and GABARAP, was observed (P< .001 compared with the sham group) and was associated with neuronal cell death in normothermic ischemic conditions. In hypothermic ischemic conditions, the autophagy inhibitory protein Bcl-2 was powerfully induced (P< .001 compared with the sham group) and was associated with blunted expression of BCLN1 and GABARAP and neuronal cell survival. The double-label fluorescent immunocytochemical studyrevealed that immunoreactivitiy for BCLN1, Bcl-2, and GABARAP was induced in the same motor neurons. These data suggest that the prolonged induction of autophagy might be a potential factor responsible for delayed motor neuron death, and the induction of the autophagy inhibitory protein Bcl-2 using hypothermia might limit autophagy and protect against delayed motor neuron death.

Hydrogen sulfide inhibits homocysteine-induced endoplasmic reticulum stress and neuronal apoptosis in rat hippocampus via upregulation of the BDNF-TrkB pathway.

Homocysteine (Hcy) can elicit neuronal cell death, and hyperhomocysteinemia is a strong independent risk factor for Alzheimer's disease. The aim of this study was to examine the effects of hydrogen sulfide (H2S) on Hcy-induced endoplasmic reticulum (ER) stress and neuronal apoptosis in rat hippocampus. Adult male SD rats were intracerebroventricularly (icv) injected with Hcy (0.6 μmol/d) for 7 d. Before Hcy injection, the rats were treated with NaHS (30 or 100 μmol·kg(-1)·d(-1), ip) and/or k252a (1 μg/d, icv) for 2 d. The apoptotic neurons were detected in hippocampal coronal slices with TUNEL staining. The expression of glucose regulated protein 78 (GRP78), C/EBP homologous protein (CHOP), cleaved caspase-12, and BDNF in the hippocampus were examined using Western blotting assays. The generation of H2S in the hippocampus was measured with the NNDPD method. Hcy markedly inhibited the production of endogenous H2S and increased apoptotic neurons in the hippocampus. Furthermore, Hcy induced ER stress responses in the hippocampus, as indicated by the upregulation of GRP78, CHOP, and cleaved caspase-12. Treatment with the H2S donor NaHS increased the endogenous H2S production and BDNF expression in a dose-dependent manner, and significantly reduced Hcy-induced neuronal apoptosis and ER stress responses in the hippocampus. Treatment with k252a, a specific inhibitor of TrkB (the receptor of BDNF), abolished the protective effects of NaHS against Hcy-induced ER stress in the hippocampus. H2S attenuates ER stress and neuronal apoptosis in the hippocampus of Hcy-treated rats via upregulating the BDNF-TrkB pathway.

Natural antisense transcripts regulate the neuronal stress response and excitability.

Neurons regulate ionic fluxes across their plasma membrane to maintain their excitable properties under varying environmental conditions. However, the mechanisms that regulate ion channels abundance remain poorly understood. Here we show that pickpocket 29 (ppk29), a gene that encodes a Drosophila degenerin/epithelial sodium channel (DEG/ENaC), regulates neuronal excitability via a protein-independent mechanism. We demonstrate that the mRNA 3'UTR of ppk29 affects neuronal firing rates and associated heat-induced seizures by acting as a natural antisense transcript (NAT) that regulates the neuronal mRNA levels of seizure (sei), the Drosophila homolog of the human Ether-à-go-go Related Gene (hERG) potassium channel. We find that the regulatory impact of ppk29 mRNA on sei is independent of the sodium channel it encodes. Thus, our studies reveal a novel mRNA dependent mechanism for the regulation of neuronal excitability that is independent of protein-coding capacity. DOI: http://dx.doi.org/10.7554/eLife.01849.001.

Differences in c-Jun N-terminal kinase recognition and phosphorylation of closely related stathmin-family members

The stathmin (STMN) family of tubulin-binding phosphoproteins are critical regulators of interphase microtubule dynamics and organization in a broad range of cellular processes. c-Jun N-terminal kinase (JNK) signalling to STMN family proteins has been implicated specifically in neuronal maturation, degeneration and cell stress responses more broadly. Previously, we characterized mechanisms underlying JNK phosphorylation of STMN at proline-flanked serine residues (Ser25 and Ser38) that are conserved across STMN-like proteins. In this study, we demonstrated using in vitro kinase assays and alanine replacement of serine residues that JNK phosphorylated the STMN-like domain (SLD) of SCG10 on Ser73, consistent with our previous finding that STMN Ser38 was the primary JNK target site. In addition, we confirmed that a JNK binding motif (41KKKDLSL47) that facilitates JNK targeting of STMN is conserved in SCG10. In contrast, SCLIP was phosphorylated by JNK primarily on Ser60 which corresponds to Ser25 on STMN. Moreover, although the JNK-binding motif identified in STMN and SCG10 was not conserved in SCLIP, JNK phosphorylation of SCLIP was inhibited by a substrate competitive peptide (TI-JIP) highlighting kinase-substrate interaction as required for JNK targeting. Thus, STMN and SCG10 are similarly targeted by JNK but there are clear differences in JNK recognition and phosphorylation of the closely related family member, SCLIP.

Temperature-induced stress response in Lymantria dispar neurosecretory neurons

The release of neurosecretory material from A2 neurosecretory neurons (NSNs) was stimulated in Lymantria dispar fourth instar caterpillars exposed to a temperature of 35 °C for 1, 12, and 24 h, as well as those allowed recover after exposure (12 h at 35 °C, then 12 h at 23 °C). The levels of 2 protein forms with the same molecular mass as bombyxin (3-4 and 4-5 kDa) increased with prolonged exposure to 35 °C. The second band was present only in the groups exposed to this stressor. There was intensified synthetic activity and a low level of secretion in L2' NSNs after exposure to 35 °C. We previously found these NSNs to be immunopositive for prothoracicotropic neurohormone. After this stress, densitometric analysis revealed a decreased amount of the 11-12 kDa isoform (present in the control group). The new isoform (13-15 kDa), expressed after exposure of the insects to a high temperature, increased in amount with prolonged exposure and after recovery at 23 °C. Short-term exposure of caterpillars to high temperatures (35 °C) is a stressor and activates carbohydrate metabolism, while PTTH immunopositive NSNs are secretory-inactive during acute thermal stress regimes.

Interventions that Improve Body and Brain Bioenergetics for Parkinson's Disease Risk Reduction and Therapy

Studies of Parkinson's disease (PD) patients, animal models and pathogenic actions of genetic mutations that cause familial PD have established that neuronal bioenergetics are compromised with brainstem and midbrain monoaminergic neurons being particularly vulnerable. Peripheral insulin resistance and diabetes in midlife may increase the risk of PD, and diet and lifestyle changes that increase insulin sensitivity (exercise and intermittent energy restriction) can counteract neurodegenerative processes and improve functional outcome in animal models. Insulin sensitizing glucagon-like peptide 1 (GLP-1) analogs are beneficial in animal models of PD, and the results of an initial clinical trial in PD patients are promising. In addition to improving peripheral and brain energy metabolism, exercise, intermittent energy restriction and GLP-1 analogs may bolster neuronal adaptive stress response pathways that enhance neurotrophic signaling, DNA repair, proteostasis and mitochondrial biogenesis.

Lose dose genistein inhibits glucocorticoid receptor and ischemic brain injury in female rats

Although acute bolus of genistein treatment has been shown to protect against neuronal damage in experimental brain injury animal models, chronic continuous low dose treatment of genistein on ischemic brain injury has not been well elucidated. In the present study, female rats were received either pure genistein (0.1mg/kg/day via osmotic minipumps) or placebo at the time of ovariectomy, and transient forebrain ischemia was induced 7days later. Results demonstrated that genistein treatment for 14days significantly improved ischemic neuronal survival in hippocampal CA1 region of ovariectomized rats. Glucocorticoid receptor (GR) is a member of the adrenal steroid hormone receptor, which is highly expressed in the rat hippocampus. Activation of the GR plays a critical role in the neuronal stress responses, including ischemic brain damage. This study therefore examined the potential mechanisms by which genistein regulates GR signaling, including the protein distribution and receptor activation in hippocampus following ischemic reperfusion (I/R). Results showed that GR expression in the ovariectomized rats was excessively increased both in neurons (I/R 6h) and activated microglial cells (I/R 7d) in hippocampal CA1 region. Genistein treatment significantly attenuated GR induction and the enhanced GR nuclear translocation and DNA-binding capacity. The effects of genistein on the GR levels was accompanied with decreased blood plasma levels of corticosterone (primary glucocorticoid in rodents) and coupled to an E3 ubiquitin ligase Mdm2 targeted proteasomal degradation of GR, because genistein treatment could enhance the GR–Mdm2 interaction and the ubiquitination level of GR protein. In addition, our results indicated that genistein markedly prevented the excessive activation of microglia in CA1 sector. These results demonstrate the neuroprotective action of chronic low dose genistein replacement against ischemic brain damage, and a potential mechanism associated with the inhibition of both neuronal and microglial GR signaling following ischemic stress.

MRNA redistribution during permanent focal cerebral ischemia.

Translation arrest occurs in neurons following focal cerebral ischemia and is irreversible in penumbral neurons destined to die. Following global cerebral ischemia, mRNA is sequestered away from 40S ribosomal subunits as mRNA granules, precluding translation. Here, we investigated mRNA granule formation using fluorescence in situ histochemistry out to 8 h permanent focal cerebral ischemia using middle cerebral artery occlusion in Long Evans rats with and without diabetes. Neuronal mRNA granules colocalized with PABP, HuR, and NeuN, but not 40S or 60S ribosomal subunits, or organelle markers. The volume of brain with mRNA granule-containing neurons decreased exponentially with ischemia duration, and was zero after 8 h permanent focal cerebral ischemia or any duration of ischemia in diabetic rats. These results show that neuronal mRNA granule response has a limited range of insult intensity over which it is expressed. Identifying the limits of effective neuronal stress response to ischemia will be important for developing effective stroke therapies.

Epilepsy: neuroinflammation, neurodegeneration, and APOE genotype

BackgroundPrecocious development of Alzheimer-type neuropathological changes in epilepsy patients, especially in APOE ϵ4,4 carriers is well known, but not the ways in which other APOE allelic combinations influence this outcome. Frozen and paraffin-embedded tissue samples resected from superior temporal lobes of 92 patients undergoing temporal lobectomies as a treatment for medication-resistant temporal lobe epilepsy were used in this study. To determine if epilepsy-related changes reflect those in another neurological condition, analogous tissue samples harvested from 10 autopsy-verified Alzheimer brains, and from 10 neurologically and neuropathologically normal control patients were analyzed using immunofluorescence histochemistry, western immunoblot, and real-time PCR to determine genotype effects on neuronal number and size, neuronal and glial expressions of amyloid β (Aβ) precursor protein (βAPP), Aβ, apolipoprotein E (ApoE), S100B, interleukin-1α and β, and α and β secretases; and on markers of neuronal stress, including DNA/RNA damage and caspase 3 expression.ResultsAllelic combinations of APOE influenced each epilepsy-related neuronal and glial response measured as well as neuropathological change. APOE ϵ3,3 conferred greatest neuronal resilience denoted as greatest production of the acute phase proteins and low neuronal stress as assessed by DNA/RNA damage and caspase-3 expression. Among patients having an APOE ϵ2 allele, none had Aβ plaques; their neuronal sizes, like those with APOE ϵ3,3 genotype were larger than those with other genotypes. APOE ϵ4,4 conferred the weakest neuronal resilience in epilepsy as well as in Alzheimer patients, but there were no APOE genotype-dependent differences in these parameters in neurologically normal patients.ConclusionsOur findings provide evidence that the strength of the neuronal stress response is more related to patient APOE genotype than to either the etiology of the stress or to the age of the patient, suggesting that APOE genotyping may be a useful tool in treatment decisions.

JNK3 Couples the Neuronal Stress Response to Inhibition of Secretory Trafficking

Secretory trafficking through the Golgi complex is critical for neuronal development, function, and stress response. Altered secretion is associated with the pathogenesis of various neurological diseases. We found that c-Jun amino-terminal kinase 3 (JNK3) inhibited secretory trafficking by promoting the depletion of phosphatidylinositol 4-phosphate (PI4P) in the Golgi complex of COS7 cells and primary rat neurons. Exposure of cultured primary rat neurons to excitotoxic concentrations of NMDA (N-methyl-d-aspartate), an agonist of a class of ionotropic glutamate receptors, or overexpression of zD17 (a palmitoyl transferase) resulted in JNK3 palmitoylation and association with the Golgi complex. Analysis of mutant constructs of JNK3 indicated that Golgi association was independent of its kinase activity but depended on its palmitoylation. The association of JNK3 with the Golgi in cultured neurons decreased the secretory trafficking of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluR1 (glutamate receptor subunit 1), a component of ionotropic glutamate receptors found at glutamatergic synapses. Palmitoylated JNK3 bound to the phosphatase Sac1, increasing its abundance at the Golgi and thereby decreasing the abundance of PI4P, a lipid necessary for post-Golgi trafficking. Disrupting the JNK3-Sac1 interaction with two synthetic peptides prevented the loss of surface GluR1 and preserved synaptic integrity in cultured neurons exposed to NMDA. Together, our results suggest that JNK3 participates in an adaptive response to neuronal hyperexcitation by impeding secretory trafficking at the Golgi complex.

Protective neuronal induction of ATF5 in endoplasmic reticulum stress induced by status epilepticus

Activating transcription factor 5 (ATF5) is a basic-leucine-zipper transcription factor of the ATF/CREB family. The Atf5 gene generates two transcripts, Atf5α and Atf5β, of which Atf5α is known to be selectively translated upon endoplasmic reticulum stress response in non-neuronal cells. ATF5 is highly expressed in the developing brain where it modulates proliferation of neural progenitor cells. These cells show a high level of ATF5 that has to decrease to allow them to differentiate into mature neurons or glial cells. This has led to the extended notion that differentiated neural cells do not express ATF5 unless they undergo tumourigenic transformation. However, no systematic analysis of the distribution of ATF5 in adult brain or of its potential role in neuronal endoplasmic reticulum stress response has been reported. By immunostaining here we confirm highest ATF5 levels in neuroprogenitor cells of the embryonic and adult subventricular zone but also found ATF5 in a large variety of neurons in adult mouse brain. By combining Atf5 in situ hybridization and immunohistochemistry for the neuronal marker NeuN we further confirmed Atf5 messenger RNA in adult mouse neurons. Quantitative reverse transcriptase polymerase chain reaction demonstrated that Atf5α is the most abundant transcript in adult mouse encephalon and injection of the endoplasmic reticulum stress inducer tunicamycin into adult mouse brain increased neuronal ATF5 levels. Accordingly, ATF5 levels increased in hippocampal neurons of a mouse model of status epilepticus triggered by intra-amygdala injection of kainic acid, which leads to abnormal hippocampal neuronal activity and endoplasmic reticulum stress. Interestingly, ATF5 upregulation occurred mainly in hippocampal neuronal fields that do not undergo apoptosis in this status epilepticus model such as CA1 and dentate gyrus, thus suggesting a neuroprotective role. This was confirmed in a primary neuronal culture model in which ATF5 overexpression resulted in decreased endoplasmic reticulum stress-induced apoptosis and the opposite result was achieved by Atf5 RNA interference. Furthermore, in vivo administration of the eIF2α phosphatase inhibitor salubrinal resulted in increased ATF5 hippocampal levels and attenuated status epilepticus-induced neuronal death in the vulnerable CA3 subfield. In good agreement with the neuroprotective effect of increased ATF5, we found that apoptosis-resistant epileptogenic foci from patients with temporal lobe epilepsy also showed increased levels of ATF5. Thus, our results demonstrate that adult neurons express ATF5 and that they increase its levels upon endoplasmic reticulum stress as a pro-survival mechanism, thus opening a new field for neuroprotective strategies focused on ATF5 modulation.

Exposure to extremely low frequency (50 Hz) electromagnetic field changes the survival rate and morphometric characteristics of neurosecretory neurons of the earthworm Eisenia foetida (Oligochaeta) under illumination stress

An in vivo model was set up to establish the behavioral stress response (rate of survival) and morphometric characteristics of A1 protocerebral neurosecretory neurons (cell size) of Eisenia foetida (Oligochaeta) as a result of the synergetic effect of extremely low frequency electromagnetic fields (ELF-EMF - 50 Hz, 50 μT, 17 V/m and 50 Hz, 150 μT, 17 V/m, respectively) and constant illumination (420-450 lux). If combined, these two stressors significantly (p<0.05) increased the survival rate of E. foetida in the 150 μT-exposed animals, because of delayed caudal autotomy reflex, an indicator of stress response. In addition, morphometric analysis indicated that there were changes in the protocerebral neurosecretory cells after exposure to the ELF-EMF. The present data support the view that short-term ELF-EMF exposure in “windows” of intensity is likely to stimulate the immune and neuroendocrine response of E. foetida.

IL-1RAcPb signaling regulates adaptive mechanisms in neurons that promote their long-term survival following excitotoxic insults

Excitotoxicity is a major component of neurodegenerative diseases and is typically accompanied by an inflammatory response. Cytokines IL-1alpha and IL-1beta are key regulators of this inflammatory response and modulate the activity of numerous cell types, including neurons. IL-1RAcPb is an isoform of IL-1RAcP expressed specifically in neurons and promotes their survival during acute inflammation. Here, we investigated in vivo whether IL-1RAcPb also promotes neuronal survival in a model of excitotoxicity. Intrastriatal injection of kainic acid (KA) in mice caused a strong induction of IL-1 cytokines mRNA in the brain. The stress response of cortical neurons at 12 h post-injection, as measured by expression of Atf3, FoxO3a, and Bdnf mRNAs, was similar in WT and AcPb-deficient mice. Importantly however, a delayed upregulation in the transcription of calpastatin was significantly higher in WT than in AcPb-deficient mice. Finally, although absence of AcPb signaling had no effect on damage to neurons in the cortex at early time points, it significantly impaired their long-term survival. These data suggest that in a context of excitotoxicity, stimulation of IL-1RAcPb signaling may promote the activity of a key neuroprotective mechanism.

MARCH5 inactivation supports mitochondrial function during neurodegenerative stress

Neuronal cell death is accompanied by mitochondrial dysfunction with mitochondrial maintenance critical to neuronal survival. The mitochondrial ubiquitin ligase MARCH5 has dual roles in the upkeep of mitochondrial function. MARCH5 is involved in targeted degradation of proteins harmful to mitochondria and impacts mitochondrial morphology upstream of the fission protein Drp1. In a neuronal cell model, dominant-negative MARCH5 prevents mitochondrial fragmentation during neurodegenerative stress induced by the neuron-specific reactive oxygen generator 6-hydroxydopamine, the complex I inhibitor rotenone or Alzheimer’s-related amyloid beta peptide. In addition, preservation of mitochondrial function in terms of membrane potential and lower reactive oxygen generation was observed following inactivation of MARCH5. Our findings connect MARCH5 to neuronal stress responses and further emphasize the link between mitochondrial dynamics and function.

Neurotoxin‐induced selective ubiquitination and regulation of MEF2A isoform in neuronal stress response

The myocyte enhancer factor 2A-D (MEF2) proteins are members of the MCM1-agamous-deficiens-serum response factor family of transcription factors. Various MEF2 isoform proteins are enriched in neurons and exhibit distinct patterns of expression in different regions of the brain. In neurons, MEF2 functions as a converging factor to regulate many neuronal functions including survival. MEF2 activities are tightly controlled in neurons in response to stress. Whether stress signal may differentially regulate MEF2s remains largely unknown. In this work, we showed that MEF2A, but not MEF2C or MEF2D, was modified by ubiquitination in dopaminergic neuronal cell line SN4741 cells. MEF2A was ubiquitinated at its N'-terminus, and the ubiquitination of MEF2A was first detectable in the nuclear compartment and later in the cytoplasm. Ubiquitination of MEF2A correlated with reduced DNA-binding activity and transcriptional activity. More importantly, disturbing the degradation of ubiquitinated MEF2A through proteasome pathway by neurotoxins known to induce Parkinson's disease features in model animals caused accumulation of ubiquitinated MEF2A, reduced MEF2 activity, and impaired cellular viability. Our work thus provides the first evidence to demonstrate an isoforms-specific regulation of MEF2s by ubiquitination-proteasome pathway in dopaminergic neuronal cell by neurotoxins, suggesting that stress signal and cellular context-dependent dysregulation of MEF2s may underlie the loss of neuronal viability.

Autophagy and phagocytosis-like cell cannibalism exert opposing effects on cellular survival during metabolic stress

Understanding mechanisms controlling neuronal cell death and survival under conditions of altered energy supply (e.g., during stroke) is fundamentally important for the development of therapeutic strategies. The function of autophagy herein is unclear, as both its beneficial and detrimental roles have been described. We previously demonstrated that loss of AMP-activated protein kinase (AMPK), an evolutionarily conserved enzyme that maintains cellular energy balance, leads to activity-dependent degeneration in neuronal tissue. Here, we show that energy depletion in Drosophila AMPK mutants results in increased autophagy that convincingly promotes, rather than rescues, neurodegeneration. The generated excessive autophagic response is accompanied by increased TOR and S6K activity in the absence of an AMPK-mediated negative regulatory feedback loop. Moreover, energy-depleted neurons use a phagocytic-like process as a means to cellular survival at the expense of surrounding cells. Consequently, phagocytosis stimulation by expression of the scavenger receptor Croquemort significantly delays neurodegeneration. This study thus reveals a potentially novel strategy for cellular survival during conditions of extreme energy depletion, resembling xeno-cannibalistic events seen in metastatic tumors. We provide new insights into the roles of autophagy and phagocytosis in the neuronal metabolic stress response and open new avenues into understanding of human disease and development of therapeutic strategies.

Unilateral pallidal stimulation in a patient with truncal dystonia

Dystonia has been defined as a syndrome of involuntary, sustained muscle contractions affecting one or more sites of the body, frequently causing twisting and repetitive movements or abnormal postures. Dystonia is also a clinical sign that can be the presenting or prominent manifestation of many neurodegenerative and neurometabolic disorders. Etiological categories include primary dystonia, secondary dystonia, heredodegenerative diseases with dystonia, and dystonia plus. Primary dystonia includes syndromes in which dystonia is the sole phenotypic manifestation with the exception that tremor can be present as well. Most primary dystonia begins in adults, and approximately 10% of probands report one or more affected family members. Many cases of childhood- and adolescent-onset dystonia are due to mutations in TOR1A and THAP1. Mutations in THAP1 and CIZ1 have been associated with sporadic and familial adult-onset dystonia. Although significant recent progress had been made in defining the genetic basis for most of the dystonia-plus and heredodegenerative diseases with dystonia, a major gap remains in understanding the genetic etiologies for most cases of adult-onset primary dystonia. Common themes in the cellular biology of dystonia include G1/S cell cycle control, monoaminergic neurotransmission, mitochondrial dysfunction, and the neuronal stress response.