Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative syndrome of unknown etiology that most commonly affects people in middle and high age. The hallmark of ALS is a progressive and simultaneous loss of upper and lower motor neurons in the central nervous system that leads to a progressive muscle atrophy, paralysis and death usually by respiratory failure. ALS is not a pure motor neuronal syndrome; it extends beyond the motor system and affects extramotor areas of the brain as well. The majority of the patients suffer from a sporadic ALS disease (SALS) while in at least ten percent the disease appears in a familial form (FALS). Mutations in the gene encoding the antioxidant enzyme superoxide dismutase-1 (SOD1) are the most common cause of FALS. More than 165 SOD1 mutations have been described, and these confer the enzyme a cytotoxic gain of function. Evidence suggests that the toxicity results from structural instability which makes the mutated enzyme prone to misfold and form aggregates in the spinal cord and brain motor neurons. Recent studies indicate that the wild-type human SOD1 protein (wt-hSOD1) has the propensity to develop neurotoxic features. The aim of the present study was to investigate if wt-hSOD1 is involved in the pathogenesis of SALS and FALS patients lacking SOD1 mutations and to evaluate the neurotoxic effect of misfolded wt-hSOD1 protein in vivo by generating a transgenic wt-hSOD1 mice model. We produced specific SOD1-peptide-generated antibodies that could discriminate between the misfolded and native form of the enzyme and optimized a staining protocol for detection of misfolded wt-hSOD1 by immunohistochemistry and confocal microscopy of brain and spinal cord tissue. We discovered that aggregates of misfolded wt-hSOD1 were constitutively present in the cytoplasm of motor neurons in all investigated SALS patients and in FALS patients lacking SOD1 gene mutations. Interestingly, the misfolded wt-hSOD1 aggregates were also found in some motor neuron nuclei and in the nuclei of the surrounding glial cells, mainly astrocytes but also microglia and oligodendrocytes, indicating that misfolded wt-hSOD1 protein aggregates may exert intranuclear toxicity. We compared our findings to FALS with SOD1 mutations by investigating brain and spinal cord tissue from patients homozygous for the D90A SOD1 mutation, a common SOD1 mutation that encodes a stable SOD1 protein with a wild-type-like enzyme activity. We observed a similar morphology with a profound loss of motor neurons and aggregates of misfolded SOD1 in the remaining motor neuron. Interestingly, we found gliosis and microvacuolar degeneration in the superficial lamina of the frontal and temporal lobe, indicating a possible frontotemporal lobar dementia in addition to the ALS disorder. Our morphological and biochemical findings were tested in vivo by generating homozygous transgenic mice that over expressed wt-hSOD1. These mice developed a fatal ALS-like disease, mimicking the one seen in mice expressing mutated hSOD1. The wt-hSOD1 mice showed a slower weight gain compared to non-transgenic mice and developed a progressive ALS-like hind-leg paresis. Aggregates of misfolded wt-hSOD1 were found in the brain and spinal cord neurons similar to those in humans accompanied by a loss of 41 % of motor neurons compared to non-transgenic litter mates. In conclusion, we found misfolded wt-hSOD1 aggregates in the cytoplasm and nuclei of motor neurons and glial cells in all patients suffering from ALS syndrome. Notable is the fact that misfolded wt-hSOD1 aggregates were also detected in FALS patients lacking SOD1 mutations indicating a role for SOD1 even when other genetic mutations are present. The neurotoxicity of misfolded wt-hSOD1 protein was confirmed in vivo by wt-hSOD1 transgenic mice that developed a fatal ALS-like disease. Taken together, our results support the notion that misfolded wt-hSOD1 could be generally involved and play a decisive role in the pathogenesis of all forms of ALS.

Doctor of Philosophy / Abstract Neurodegenerative disorders are a diverse group of disorders that affect specific subsets of neurons. Motor neuron diseases, neurodegenerative disorders of motor neurons, are seen commonly as sporadic cases and less frequently as familial disease forms. The familial forms show genetic and phenotypic heterogeneity. Clinically motor neuron diseases may be seen as rapidly progressive disorders like amyotrophic lateral sclerosis, ALS or slowly progressive disorders like hereditary motor neuropathies, HMN. The only proven causes for motor neuron diseases are gene mutations that lead to motor neuron degeneration in familial disease forms. Only some of these genes have been identified and have contributed greatly to our understanding of the neurobiology of familial and sporadic disease forms. Identification of additional disease causing genes would help enhance our knowledge of the pathophysiological mechanisms underlying all forms of motor neuron disorders, which would lead to early diagnoses, effective prophylaxis and efficient therapies for these disorders. This study aimed to find gene mutations that cause rapid and slowly progressive familial motor neuron disorders in Australian families and to determine their relevance to sporadic forms of motor neuron disease. The familial forms of ALS show reduced disease penetrance, that is, not all gene mutation carriers manifest the disease. This study examines ALS penetrance in a group of Australian families. The most frequently observed mutations in ALS families are cytosolic superoxide dismutase/SOD1 gene mutations. In a collection of ALS families in our centre, families without the common SOD1 gene mutations were genotyped for other ALS genes and loci and studied using genetic linkage and haplotype analyses. Studies in a large Australian ALS family further confirmed genetic heterogeneity in non-SOD familial ALS, all known autosomal dominant ALS genes and chromosomal loci were excluded as cause of disease in this family. Such families can be studied further to identify additional disease genes and loci mapped in other ALS families. These families represent powerful resources for identification of additional ALS genes. Identifying the pathogenic genes in families with reduced disease penetrance may be more relevant to sporadic forms of disease. dHMN is a chronic neurodegenerative disorder predominantly affecting motor neurons. In a large Australian dHMN family, all the known dHMN genes and chromosomal loci were excluded as cause of disease. A genome wide microsatellite screen was performed in this family and genetic linkage was established to a novel 12.98 Mb locus on chromosome 7q34.2-q36. Candidate genes in this large interval will be screened based on their function and expression profile. Identification of a new dHMN locus provides the basis for future identification of a novel gene involved in motor neuron degeneration. Genes in dHMN have been shown to be pathogenic in ALS and Charcot Marie Tooth syndromes. The new locus for dHMN mapped in this project would lead to identification of a novel dHMN gene, which may elucidate the pathogenesis underlying a wide range of neurodegenerative disorders.

Heidelberg, Univ., Diss., 2007.

Texte remanié de: Diss.--Fakultät für Philologie--Bochum--Ruhr-Universität, 1994. / Bibliogr. p. 252-264. Index.

Die vorliegende Arbeit gehört zu den Kulturstudien Deutsch als Fremdsprache (DaF), die auf eine kulturwissenschaftlich ausgerichtete Neukonzeption der traditionellen Landeskunde abzielen. Ihr vornehmlicher wissenschaftlicher Gegenstand sind die kulturellen Deutungsmuster, die als ein Fundus präsupponierter Wissensfragmente den Sinnzuschreibungsprozessen einer Kommunikationsgemeinschaft zugrunde liegen. Diese Arbeit stellt eine kulturwissenschaftliche Deutungsmusteranalyse vor, die auf eine methodisch kontrollierte Annäherung und exakte Beschreibung dieser textuell verankerten Muster fokussiert. Dazu wird eine begriffliche Ausdifferenzierung der theoretischen Fundierung des Deutungsmusterkonzeptes von C. Altmayer (2004) vorgenommen. Die Deutungsmusteranalyse wird anhand des exemplarischen Fallbeispiels \"Europa\" durchgeführt, das im deutschsprachigen Mediendiskurs zum EU-Beitritt der Türkei untersucht wurde. Das verwendete Materialkorpus besteht aus Texten (d.h. Artikel, Karikaturen, Bilder) zum EU-Beitritt der Türkei von 2002-2004 in den deutschen Printmedien ZEIT, STERN, FAZ, SPIEGEL und der BILD-Zeitung sowie dem ZEIT-Online-Leserforum „EU-Beitritt der Türkei“.

Made available in DSpace on 2014-06-11T19:30:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2010-09-10Bitstream added on 2014-06-13T21:01:04Z : No. of bitstreams: 1 cavalieri_sd_dr_botfca.pdf: 541032 bytes, checksum: 35c98291dc7bcdb9b1ec86f4f88d72ba (MD5) / Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP) / O estudo da seletividade e dos efeitos secundários dos herbicidas nas culturas agrícolas é de extrema importância para o sucesso da agricultura. No presente trabalho, três experimentos foram realizados. O primeiro, conduzido em casa-de-vegetação localizada na Faculdade de Ciências Agronômicas, UNESP, Campus de Botucatu (SP), teve como objetivo avaliar o efeito de formulações comerciais de glyphosate em parâmetros nutricionais e acúmulo de matéria seca de duas cultivares de soja RR resistentes ao glyphosate. Os tratamentos avaliados resultaram do arranjo fatorial entre formulações de glyphosate (Roundup Original®, Roundup Ready®, Roundup Transorb®, Roundup WG®, Roundup Ultra® e Zapp Qi®), mais uma testemunha e cultivares de soja RR (CD 225 RR e V Max RR), conduzidos em delineamento de blocos completos casualizados com seis repetições. As aplicações dos herbicidas ocorreram quando as plantas de soja apresentavam-se no estádio V3 (25 dias após a emergência), na dosagem de 960 g e.a. ha-1. Transcorridos 15 dias após o tratamento, a parte aérea das plantas de soja foi colhida e seca em estufa. Depois de secas, obtiveram-se os dados de massa da matéria seca de hastes, folhas e parte aérea (hastes + folhas), sendo em seguida o material triturado e enviado para laboratório para análise dos teores de macronutrientes (N, P, K, Ca, Mg e S) e micronutrientes (Cu, Fe, Mn, Zn e B). Após isso, de posse dos resultados das análises laboratoriais, calculou-se o acúmulo de nutrientes na parte aérea de cada planta presente nos vasos. De forma geral, o acúmulo de macronutrientes, micronutrientes e matéria seca na parte aérea das plantas de soja sempre foi maior na cultivar V Max RR em relação à CD 225 RR. As formulações Roundup Ready® e Roundup Ultra®, não apresentaram problemas no que diz respeito ao acúmulo de nutrientes e matéria seca na parte aérea... / The study of selectivity and secondary effects of herbicides on crops is extremely important to the success of agriculture. In this study, three experiments were conducted. The first one, carried out in a greenhouse located at the College of Agronomic Sciences, UNESP, Botucatu (SP), aimed to evaluate the effect of commercial formulations of glyphosate on nutritional status and dry matter accumulations in two glyphosate-resistant soybeans cultivars (GR). The treatments were arranged in a factorial arrangement involving six commercial formulations of glyphosate Roundup Original®, Roundup Ready®, Roundup Transorb®, Roundup WG®, Roundup Ultra® and Zapp Qi® plus a control treatment, and two soybean cultivars (CD 225 RR and V Max RR), arranged in a randomized complete block design replicated six times. The herbicide applications occurred when the soybean plants were at V3 growth stage (25 days after emergence) using a dose of 960 g a.e. ha-1. After 15 days after application, the shoot of soybeans was harvested and dried in an oven. Once dried, we obtained data of dry matter of stems, leaves and shoots (stems + leaves), and then the plants were crushed and sent to the laboratory for analysis of macronutrients (N, P, K, Ca, Mg and S) and micronutrients (Cu, Fe, Mn, Zn and B). After that, ownership of the results of nutritional analysis, we calculated the accumulation of nutrients in the shoots in each plant of the pots. In general, the accumulation of macronutrients, micronutrients and dry matter in the shoot of soybean plants was always greater in V Max RR cultivar than CD 225 RR cultivar. The formulations Roundup Ready®, Roundup Ultra® and Zapp QI® showed no problems in regard to the accumulation of nutrients in shoots of cultivars. Furthermore, the Roundup Original®, Roundup Transorb® and Roundup WG® formulations caused the greatest damage to the nutrition provided the cultivars... (Complete abstract click electronic access below)

Amyotrofisk lateralskleros (ALS) är en grupp motorneuronsjukdomar som leder till degenerering och död av centrala och perifera motoriska neuroner. ALS patienter drabbas av muskelsvaghet, muskelförtvining i skelettmuskulatur och förlamning. Överlevnaden efter diagnosen är ca två år i de flesta fall. I Sverige insjuknar årligen drygt 200 personer i ALS. Komplexa genetiska faktorer till exempel ALS-kopplade gener är avgörande för utvecklingen av ALS. Några miljöfaktorer har föreslagits som riskfaktorer för sporadisk ALS. På grund av en mycket komplex etiologi i sjukdomsuppkomst och utveckling saknas det än idag effektiv terapi för ALS. Vad gäller primära läkemedel som används i ALS-terapi är endast riluzol godkänd i Sverige idag. Edaravone och masitinib som har visat svag till moderat effekt och utifrån kontrollerade kliniska studier har de en neuroprotektiv roll som förlänger överlevnadstiden något. Syftet med föreliggande examensarbete var att undersöka den senaste utvecklingen kring behandlingar av ALS samt att utvärdera effekten av edaravone och masitinib samt jämföra deras respektive effektivitet med standardpreparatet riluzol. Totalt valdes och analyserades 6 kliniska studier, där 3 studier utvärderade effektiviteten av behandling med olika doser riluzol, i en klinisk studie undersöktes biverkningsspektrumet av riluzol, samt en klinisk studie med masitinib och en med edaravone. Behandling med riluzol resulterade i ökad överlevnad hos ALS patienter med 20 % (Studie 1) och 35 % (Studie 2) efter 12 månader. Resultaten från en stor klinisk studie (Studie 3) som inkluderade ett stort antal ALS-patienter visade att riluzol tolereras mycket väl vid dosen 100 mg/dag (50 mg x 2 per dag). Resultaten från Studie 4 visade att behandling med 100 mg/dag riluzol förlängde fas 4 hos patienter med ALS oavsett i vilken fas av sjukdomen behandlingen påbörjades. Behandling med masitinib i dosen 4,5 mg/kg/dag + riluzol (100 mg/dag) visade signifikant effekt för ALS patienter med baseline av ALSFRS-R utveckling ˂1,1 poäng/månad och visade 27% effekt efter 48 veckor behandling. Effekten visade sig vara högre, 35% i patienter med sjukdomsutveckling kortare än 18 månader efter diagnos (Studie 5). Utifrån resultat från Studie 6 visade behandling med edaravone effekt endast i en begränsad grupp av ALS patienter, identifierade med hjälp av post-hoc analys av en tidigare fas III RCT. Däremot fanns det ingen indikation att behandling med edaravone skulle vara effektiv för en bredare grupp ALS patienter. Det är möjligt att masitinib är ett nytt läkemedel för behandling av ALS patienter som skulle kunna användas som komplement till riluzolbehandling, dock behövs fler kliniska studier för att utvärdera effekten av masitinib.  Riluzol har känd effekt – förlänger överlevnaden med 2 till 3 månader i vanliga fall av ALS. Edaravone visade svag effekt vid behandling av ALS.

La sclérose Latérale Amyotrophique (SLA) est une maladie neurodégénérative des motoneurones impliquant des facteurs environnementaux et génétiques. Notre étude porte sur l’étude des relations entre la voie de la SUMOylation post-Traductionnelle des protéines et les effets du stress oxydant et de mutants SOD1. Nous montrons tout d’abord que 2 nouveaux mutants, SOD1V31A et SOD1E121G identifiés chez des patients SLA à évolution lente, entraîne la formation d’agrégats cellulaires Ub/SUMO dans la formation des agrégats était suggérée. Nous montrons 1) que les NSC-34 exposées à un stress oxydant et exprimant SOD1 mutée présentent une modification d’expression de plusieurs gènes des voies de l’Ub/SUMO ; 2) que l’expression de SOD1 mutée réduit le pool de protéine SUMO-1 libre dans les cellules motoneuronales, possible conséquence d’une séquestration dans les agrégats ; 3) qu’inhiber la SUMOylation de SOD1 mutée réduit la quantité de cellules avec agrégats. Nos résultats indiquent qu’une meilleure connaissance de la voie de SUMO pourrait conduire à de nouvelles cibles thérapeutiques intéressantes dans la SLA. / Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease of motor neurones involving a combination of environmental and genetics factors. Ours work focuses on the relathionship between the SUMOylation pathway and the effects of oxidative stress and SOD1 mutants. We first show that 2 new mutants, SOD1V31A and SOD1E121G identified in ALS patients with a slowly progressive disease, induce the formation of Ub/SUMO positive aggregates in motor neuronal cells NSC-34. The implication of the Ub/SUMO pathways has been proposed in the formation of aggregates in ALS. We show 1) modification of expression of several genes of the Ub/SUMO pathways in NSC-34 exposed to oxidative stress and expressing various mutated SOD1 proteins; 2) that the expression of mutants SOD1 reduces free-SUMO1 concentration in motor neuronal cell, perhaps by a sequestration in aggregates; 3) that the inhibition of SUMIylation of various mutants SOD1 reduces the amount of cells with aggregates. Our results support further studies on the SUMO pathway that may lead to new therapeutics targets in ALS.

Submitted by Reginaldo Soares de Freitas (reginaldo.freitas@ufv.br) on 2017-04-26T13:22:22Z No. of bitstreams: 1 texto completo.pdf: 386408 bytes, checksum: 1d07ce98be2c52bdc785ddfdff577fa1 (MD5) / Made available in DSpace on 2017-04-26T13:22:22Z (GMT). No. of bitstreams: 1 texto completo.pdf: 386408 bytes, checksum: 1d07ce98be2c52bdc785ddfdff577fa1 (MD5) Previous issue date: 2000-08-24 / Conselho Nacional de Desenvolvimento Científico e Tecnológico / A ocorrência de plantas daninhas resistentes a herbicidas é um fato novo no Brasil. A caracterização da resistência é importante para embasar previsões e eleger métodos de manejo e controle. Desse modo, foram realizados na Universidade Federal de Viçosa, de março de 1997 a julho de 1999, quatro experimentos, objetivando de identificar biótipos resistentes e caracterizar a resistência. O primeiro experimento objetivou identificar e estudar os mecanismos envolvidos na resistência, cujos resultados indicaram resistência cruzada aos herbicidas inibidores da enzima ALS. Estudos com ALS, extraída de plantas resistentes de leiteiro, indicaram I50 superior a 3.000 μM para o imazapyr e 2.000 μM para o imazethapyr, contrastando com valores de I50 de 2 μM para aquele e 0,7 μM para este em plantas sensíveis. No segundo experimento, investigou-se a resposta dos biótipos resistentes a herbicidas com diferentes mecanismos de ação. Constatou-se que os herbicidas inibidores da ALS controlaram com eficiência o biótipo sensível, à exceção do flumetsulan; já sobre o biótipo resistente, somente o herbicida imazapyr, na maior dose, apresentou controle. Os herbicidas com mecanismos de ação distintos daqueles dos inibidores da ALS apresentaram-se altamente eficientes no controle dos biótipos resistentes e sensíveis quando aplicados de forma isolada ou em mistura. O terceiro experimento objetivou descrever uma técnica de cruzamento controlado em Euphorbia heterophylla L. Os resultados evidenciaram que as polinizações e emasculações realizadas no estádio 1 produzem grande número de ciátios com uma ou duas sementes e raramente com três. As realizadas no estádio 2, ou acima deste, garantiram o sucesso dos cruzamentos com boa produção de sementes. No quarto experimento, estudaram-se a herança, o número de genes que conferem a resistência e o grau de resistência dos biótipos homozigotos e heterozigotos resistentes. As plantas F1 mostraram-se totalmente resistentes ao herbicida, indicando que a resistência é nuclear e dominante. As plantas F2 apresentaram alta probabilidade para segregação 3:1, evidenciando que a resistência é codificada por um gene dominante. Pela aplicação de doses crescentes de imazethapyr sobre as plantas F1, calculou-se que os biótipos homozigotos resistentes e os heterozigotos apresentaram o mesmo grau de resistência para doses de até 1.600 g ha-1 desse herbicida. Os resultados permitiram concluir que a insensibilidade da enzima ALS aos herbicidas que a inibem é o principal mecanismo responsável pela resistência das plantas de Euphorbia heterophylla L. a tais produtos. Os biótipos resistentes são controlados com eficiência com herbicidas com mecanismos de ação distintos daqueles dos inibidores da ALS. A resistência é codificada por um gene dominante nuclear com dominância completa. / The occurrence of herbicide-resistant weeds is a new fact in Brazil. The characterization of the resistance is important to provide a base for previsions and select methods of management and control. Therefore, four experiments were carried out at the Universidade Federal de Viçosa, from March,1997, to July, 1999, to identify resistant biotypes and to study the mechanisms involved in resistance. The first experiment, aimed to identify and study the mechanisms involved in the resistance, had the results indicating cross resistance to ALS inhibitory herbicides. Studies with ALS, extracted from resistant plants, showed l50 superior to 3000 μM for imazapyr and 2000 μM for imazethapyr, which contrasted with l50 values of 2 μM for the former and 0.7 μM for the latter in susceptible plants. The second experiment analyzed the response of the resistant biotypes to herbicides with different modes of action. It was verified that the ALS inhibitory herbicides had efficient control over the susceptible biotypes, apart from flumetsulan; as for the resistant biotype, only the herbicide imazapyr at its highest dose, showed control. The herbicides with modes of action distinct from those ALS inhibitors were shown highly efficient on controlling susceptible and resistant biotypes when applied separately or in mixture. The third experiment aimed to describe a technique of controlled crossings in Euphorbia heterophylla L. The results showed evidence that pollination and emasculation performed at stage 1 produce a great number of ciatios with one or two seeds and rarely with three. Those performed at stage 2, or above this stage, assured the success of the crossings with a good production of seeds. In the fourth experiment, the inheritance, the number of genes that confer resistance and the degree of resistance in resistant homozygote and heterozygote biotypes, were studied. The F1 plants were shown totally resistant to the herbicide, indicating that the resistance is nuclear and dominant. The F2 plants presented a high probability for 3:1 segregation, making evident that the resistance is codified by a dominant gene. It was calculated that the biotypes resistant homozygote and heterozygote showed the -1 same degree of resistance for doses up to 1600 g ha , by means of the application of increasing doses of imazethapyr on F1 plants. The results obtained permit the conclusion that the insensitivity of the ALS enzyme to the herbicides is the primary mechanism responsible for the resistance of Euphorbia heterophylla L. to such products. The resistant biotypes are efficiently controlled by herbicides with mechanism of action distinct from those of the ALS inhibitors. The resistance is codified by a nuclear dominant gene with complete dominance.

The dysfunction of autophagy pathways has been linked to the development and progression of numerous human diseases, in particular neurological disorders and cancer. Investigating these pathological autophagy mechanisms is essential to gain insights into the underlying disease mechanisms, identify novel biomarkers, and develop targeted therapies. In this thesis, I present three manuscripts that investigate the regulatory mechanisms of autophagy machinery in human diseases. In the first manuscript (Chitiprolu et al., 2018), we investigated the mechanism of p62-mediated selective autophagic clearance of RNA stress granules implicated in Amyotrophic Lateral Sclerosis (ALS). Repeat expansions in C9ORF72, the major cause of ALS, reduce C9ORF72 levels but how this impacts stress granules is uncertain. By employing mass spectrometry, high resolution imaging and biochemical assays, we demonstrated that the autophagy receptor p62 associates with C9ORF72 to eliminate stress granules by autophagy. This requires p62 to associate with proteins that are symmetrically methylated on arginines. Patients with C9ORF72 repeat expansions accumulate symmetric arginine dimethylated proteins which co-localize with p62. This suggests that C9ORF72 initiates a cascade of ALS-linked proteins (C9ORF72, p62, SMN, FUS) to recognize stress granules for degradation by autophagy and hallmarks of a defect in this process are observable in ALS patients. The second manuscript (Guo, Chitiprolu et al., 2014) describes the mechanism by which autophagy degrades retrotransposon RNA from both long and short interspersed elements, thereby preventing new retrotransposon insertions into the genome. By employing quantitative imaging tools, we demonstrated that retrotransposon RNA localizes to RNA granules that are selectively degraded by the autophagy receptors NDP52 and p62. Mice lacking a copy of Atg6/Beclin1, a gene critical for autophagy, also accumulate both retrotransposon RNA and genomic insertions. This suggests a mechanism for the increased tumorigenesis upon autophagy inhibition and therefore a role for autophagy in tempering evolutionary change. Finally, the third manuscript (Guo, Chitiprolu et al., 2017) examines the intersection of autophagy machinery with exosome release and function in cancer metastasis. By employing dynamic light scattering, Nanosight particle tracking, electron microscopy, super-resolution imaging and Western blotting, we robustly quantified exosome identity and purity in multiple cell lines. We demonstrated that exosome production is strongly reduced in cells lacking Atg5 and Atg16L1, but this is independent of Atg7 and canonical autophagy. The effect of Atg5 on exosome production promotes the migration and in vivo metastasis of orthotopic breast cancer cells. These findings delineate autophagy-independent pathways by which autophagy-related genes can contribute to metastasis. Taken together, data presented in the three manuscripts highlight the molecular mechanisms of autophagy core machinery proteins and selective receptors such as Atg5, p62 and NDP52, in the pathogenesis of cancer and neurodegeneration. In these diseases characterized by mutations in autophagy pathways, the mechanisms we uncover provide insights into their causes and serve as potential therapeutic targets.