TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons

Nuclear clearance of TDP-43 into cytoplasmic aggregates is a key driver of neurodegeneration in amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), but the mechanisms are unclear. Here, we show that TDP-43 knockdown specifically reduces the number and motility of RAB11-positive recycling endosomes in dendrites, while TDP-43 overexpression has the opposite effect. This is associated with delayed transferrin recycling in TDP-43-knockdown neurons and decreased 2-transferrin levels in patient CSF. Whole proteome quantification identified the upregulation of the ESCRT component VPS4B upon TDP-43 knockdown in neurons. Luciferase reporter assays and chromatin immunoprecipitation suggest that TDP-43 represses VPS4B transcription. Preventing VPS4B upregulation or expression of its functional antagonist ALIX restores trafficking of recycling endosomes. Proteomic analysis revealed the broad reduction in surface expression of key receptors upon TDP-43 knockdown, including ErbB4, the neuregulin 1 receptor. TDP-43 knockdown delays the surface delivery of ErbB4. ErbB4 overexpression, but not neuregulin 1 stimulation, prevents dendrite loss upon TDP-43 knockdown. Thus, impaired recycling of ErbB4 and other receptors to the cell surface may contribute to TDP-43-induced neurodegeneration by blocking trophic signaling

CRISPR-Cas9 screens in human cells and primary neurons identify modifiers of C9ORF72 dipeptide-repeat-protein toxicity.

Hexanucleotide-repeat expansions in the C9ORF72 gene are the most common cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). The nucleotide-repeat expansions are translated into dipeptide-repeat (DPR) proteins, which are aggregation prone and may contribute to neurodegeneration. We used the CRISPR-Cas9 system to perform genome-wide gene-knockout screens for suppressors and enhancers of C9ORF72 DPR toxicity in human cells. We validated hits by performing secondary CRISPR-Cas9 screens in primary mouse neurons. We uncovered potent modifiers of DPR toxicity whose gene products function in nucleocytoplasmic transport, the endoplasmic reticulum (ER), proteasome, RNA-processing pathways, and chromatin modification. One modifier, TMX2, modulated the ER-stress signature elicited by C9ORF72 DPRs in neurons and improved survival of human induced motor neurons from patients with C9ORF72 ALS. Together, our results demonstrate the promise of CRISPR-Cas9 screens in defining mechanisms of neurodegenerative diseases

C9orf72-mediated ALS and FTD: multiple pathways to disease

The discovery that repeat expansions in the C9orf72 gene are a frequent cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has revolutionized our understanding of these diseases. Substantial headway has been made in characterizing C9orf72-mediated disease and unravelling its underlying aetiopathogenesis. Three main disease mechanisms have been proposed: loss of function of the C9orf72 protein and toxic gain of function from C9orf72 repeat RNA or from dipeptide repeat proteins produced by repeat-associated non-ATG translation. Several downstream processes across a range of cellular functions have also been implicated. In this article, we review the pathological and mechanistic features of C9orf72-associated FTD and ALS (collectively termed C9FTD/ALS), the model systems used to study these conditions, and the probable initiators of downstream disease mechanisms. We suggest that a combination of upstream mechanisms involving both loss and gain of function and downstream cellular pathways involving both cell-autonomous and non-cell-autonomous effects contributes to disease progression

The Politics of Pensions in European Social Insurance Countries

This paper analyzes national processes of pension reform in countries with systems of old-age provision largely following the Bismarckian type (Austria, France, Germany, Italy, Sweden). Operating on a defined benefit/pay-as-you-go basis and mainly financed out of wage-based social contributions, pension systems in these countries are highly vulnerable to demographic and economic pressures. Therefore, pension reform has emerged as a major issue in these countries since the early 1990s. Although there are substantial similarities in the direction of reform, the degree of policy change varies considerably even among countries with similar legacies in pension policy. As a closer inspection of national patterns of pension policy-making shows, the political feasibility of pension reforms and the degree of adjustment in pension policy critically depends on the government's ability to orchestrate a reform consensus either with the parliamentary opposition or with the trade unions. The paper tries to identify the conditions under which a "pension pact" between those actors is likely to emerge.Die vorliegende Arbeit analysiert rentenpolitische Entscheidungsprozesse in Ländern, deren Alterssicherungssysteme weitgehend dem Bismarckmodell folgen (Deutschland, Frankreich, Italien, Österreich, Schweden). Da sie typischerweise definierte Leistungen im Wege des Umlageverfahrens gewähren und sich primär über lohnabhängige Sozialbeiträge finanzieren, erweisen sich diese Systeme als vergleichsweise anfällig gegenüber ökonomischem und demographischem Problemdruck. Vor diesem Hintergrund hat das Thema "Rentenreform" in diesen Ländern spätestens seit Anfang der 90er-Jahre erheblich an Bedeutung gewonnen. Obgleich aus international vergleichender Perspektive große Gemeinsamkeiten in der Grundausrichtung der Reformen erkennbar sind, lassen sich - auch in Ländern mit ähnlich konzipierten Alterssicherungssystemen - erhebliche Unterschiede im Grad der vorgenommenen Veränderungen feststellen. Wie eine eingehendere Betrachtung der nationalen Reformpfade auf dem Feld der Rentenpolitik zeigt, hängt die politische Durchsetzbarkeit von Rentenreformen entscheidend von der Fähigkeit der Regierung ab, einen Reformkonsens mit der parlamentarischen Opposition beziehungsweise mit den Gewerkschaften herzustellen. Das Papier versucht, die Bedingungen herauszuarbeiten, unter welchen ein rentenpolitischer Konsens zwischen diesen Akteuren wahrscheinlich ist.1 Introduction 2 A Comparative Assessment of Policy Change in Bismarckian Pension Systems 3 Explaining Variation in Pension Reform Outcomes 3.1 Searching for Consensus in Pension Policy-making 3.2 Conditions for Successful Concertation 3.2.1 Pension Politics in the Partisan Arena 3.2.2 Pension Politics in the Corporatist Arena 3.3 National Patterns of Decision-making in Pension Politics 3.3.1 Sweden: Policy-oriented Bargaining 3.3.2 Italy: Corporatist Concertation in the Shadow of EMU 3.3.3 Germany: From Consensus Towards Conflict 3.3.4 Austria: Reform Blockage by the Trade Unions 3.3.5 France: Adverse Prerequisites for a Pension Consensus 4 Conclusion Reference

Chances and limitations of "benchmarking" in the reform of welfare state structures - the case of pension policy

The concept of benchmarking, originally developed as a tool to improve the performance of business enterprises by learning from others’ "best practice", is now increasingly applied in the areas of employment and social policy. Rising internal and external pressures on national welfare states, sometimes reinforced by supra-national institutions, a rapid growth of modern communication technologies and an ongoing process of ideological liberalization drive this development. Just as benchmarking between companies benchmarking between national social policies is seen as an instrument to reduce the costs of pure trial and error. However, learning from abroad is neither a sufficient nor a necessary condition for successful welfare state adjustment. First, it is only one possible factor for welfare state change next to many others. Second, it does not necessarily lead to policy change because policy makers may be unable or unwilling to implement what they have learned. Third, even if cross-national policy transfer takes place it may fail to yield the expected benefits. For a number of reasons the transferability of welfare policies across countries may be restricted. Most importantly, policy transfer may be inappropriate if policymakers do not pay sufficient attention to the different economic, social, political or ideological context in the importing country. This is especially true when it comes to the great institutional diversity of national retirement systems, which are based on highly country-specific policy mixes and which display strong interdependencies with other policy areas. Therefore, a large-scale adoption of onesize-fits-all solutions such as the World Bank’s three-pillar pension model appears to be problematic. The costs of establishing new institutional arrangements form another impediment to policy transfer. The extraordinarily high cost of financing the transition from a pay-as-you-go to a fully funded pension system is a case in point. Moreover, the benchmarking of social policies is faced with the difficulty that policy goals tend to be ambiguous or even characterized by harsh trade-offs. Pension reformers, for instance, are invariably confronted with the problem of containing rising pension costs while ensuring a decent level of social security for the elderly population. Therefore, the notion of "best practice" appears to be problematic with respect to social policy reform. Finally, policy makers must be concerned with the political risks associated with policy transfer, especially in a political minefield such as pensions. For these reasons, policy transfer between welfare states appears to be qualitatively different from transfer of "best practice" between companies. Under these conditions, the probability of (appropriate) policy transfer will hinge on two factors. First, the more the local conditions and especially the welfare arrangements differ from one country to another the more difficult and the less likely policy transfer will be. Second, exchange of information will be easier than the transfer of ideas and goals, which on their part will diffuse more easily across national borders than concrete policy instruments and institutions. In particular, the import of institutions incompatible to existing policy structures may interfere with the balance of power between societal actors and therefore meet with political resistance

The Reform of Bismarckian Pension Systems: A Comparison of Pension Politics in Austria, France, Germany, Italy and Sweden

Pension reform has emerged as a major political issue in most advanced welfare states. Sluggish economic growth and rising unemployment put public pension systems under increasing financial pressure. In combination with a rapidly ageing population in the decades to come, these pressures render major adjustements in pension policy design inevitable, especially in countries with costly earnings-related benefit arrangements. However, timely and successful adjustement is anything but guaranteed. Both cuts of pension benefits and increases in contribution levels are bound to be highly unpopular and entail massive political risks. Thus, pension politics these days is as much about adjusting pension arrangements to changing demographic and economic conditions as it is about overcoming widespread political resistance to reforms that impose tangible losses on large parts of the population. This study reveals striking differences in the extent to which pension policy makers were able to generate a sufficient political support basis for their reform initiatives. As a consequence, pension reform outcomes reach from successful restructuring of existing pension arrangements all the way down to instances of outright policy failure. By tracing the political process of pension reform in Austria, France, Germany, Italy and Sweden since the late 1980s the book also provides us with deeper insights about the factors that facilitate – or impede – social policy reforms in the context of fiscal austerity.List of Tables/List of Figures Acknowledgements Introduction 1 The Need for Pension Reform: A Problem-Oriented Perspective 1.1 Public pension arrangements under adaptational pressures 1.2 Specific vulnerabilities of Bismarckian pension systems 1.3 Options for reform 1.4 Varying degrees in the need for adjustment 2 An Empirical Overview of Policy Change in Bismarckian Pension Regimes 3 The Politics of Pension Reform: An Actor-Centred Explanatory Framework 3.1 Social policymaking in an era of retrenchment: A review of theoretical approaches 3.2 The concept of actor-centred institutionalism 3.3 The politics of pension reform 3.4 Summary of the theoretical framework 4 Sweden: Policy-Oriented Bargaining 5 Italy: CorporatistConcertation in the Shadow of EMU 6 Germany: From Consensus To Conflict 7 Austria: Reform Blockage by the Trade Unions 8 France:Adverse Prerequisites for a Pension Consensus 9 Conclusion Appendix I Summary Description of Retirement Systems (1986) Appendix If Chronology of National Pension Reforms Appendix ill Glossary of Terms Notes Bibliography Inde

Die Reform des Bismarck'schen Rentensystems: Ein rentenpolitischer Vergleich in Österreich, Frankreich, Deutschland, Italien und Schweden

This study analyzes national processes of pension reform in countries with systems of old-age provision largely following the Bismarckian type (Austria, France, Germany, Italy, and Sweden). Operating on a defined benefit/pay-as-you-go basis and mainly financed out of wage-based social contributions, pension systems in these countries are highly vulnerable to demographic and economic pressures. Therefore, pension reform has emerged as a major issue in these countries since the late 1980s. Although there are substantial similarities in the direction of reform, the degree of policy change varies considerably even among countries with similar legacies in pension policy. A closer inspection of national patterns of pension policy making shows that the political feasibility of pension reforms and the degree of adjustment in pension policy critically depends on the government's ability to orchestrate a reform consensus either with the parliamentary opposition or with the trade unions. The study tries to identify the conditions under which a “pension pact” between those actors is likely to emerge.List of tables List of figures Introduction Chapter I: The need for pension reform – a problem-oriented perspective 1.1 Public pension arrangements under adaptational pressures 1.2 Specific vulnerabilities of Bismarckian pension systems 1.3 Options for reform 1.4 Varying degrees in the need of adjustment Chapter 2: An empirical overview of policy change in Bismarckian pension regimes Chapter 3: The politics of pension reform – an actor-centered explanatory framework 3.1 Social policy-making in an era of retrenchment – a review of theoretical approaches 3.2 The concept of actor-centered institutionalism 3.3 The politics of pension reform Chapter 4: Sweden - Policy-oriented bargaining Chapter 5: Italy - Corporatist concertation in the shadow of EMU Chapter 6: Germany - From consensus towards conflict Chapter 7: Austria - Reform blockage by the trade unions Chapter 8: France - Adverse prerequisites for a pension consensus Chapter 9: Conclusion Appendix I: Summary description of retirement systems (1986) Appendix II: Chronology of national pension reforms Appendix III: Glossary of terms Bibliograph

Sequences of Policy Failures and Effective Policy Responses

The chapter examines the dynamics of policy responses and their ultimate effectiveness. It identifies typical sequences of policy failures, caused by the misfit between new problems and existing policy legacies, which may generate processes of policy learning that ultimately produce effective solutions; but it also points to instances in which policy learning is blocked by conflicts of interest or by divergent cognitive orientations in multi-actor institutional settings. Of equal importance are sequences of lateral spillovers, where the solutions to problems in one policy area generate new problems that subsequently must be dealt with in adjacent policy areas. In the 1970s and 1980s, these spillovers were most important in countries where the rise of open unemployment was mitigated by resort to early retirement and disability pensions. In analysing these sequences of policy failure, learning, and problem displacement, the chapter also compares and assesses the greater or lesser effectiveness of the policy responses actually adopted and identifies successful countries that were able to adjust to the challenges of the open economy without abandoning their welfare-state goals

What Do Unions Do to the Welfare States?

Current theories of unions are mainly theories of what unions were and did rather than theories of what unions will be and will do. Thus, the purpose of this book is to help make economic thinking about unions in Europe more forward-looking and to discuss the role that unions are likely to play in the changed economic environment of the new century. The volume consists of two reports that are the results of coordinated efforts by some of the most authoritative scholars in the field. The first study addresses a number of issues related to the question of how the primary role of trade unions—collective bargaining over wages and work conditions—is likely to evolve in the early decades of the new millennium. Starting from the widespread impression of a trend toward weakening union power, the main aspects considered by the analysis are membership, wage effects, organization and presence of unions, bargaining structure, macroeconomic performance, future scenarios, and strategies. The second study investigates the interactions between trade unions, welfare systems, and welfare reforms. The overall theme is the policy dilemma created by the many different activities of trade unions in the field of welfare provision, notably pension policies and unemployment protection.Throughout the analysis, a tension emerges between the role of unions as voice of atomistic agents and insurance providers—that may contribute to increasing aggregate welfare by remedying market failures—and as rent-seeking monopolist, underlying the intergenerational conflicts present within unions. The studies point to measures and strategies enhancing this second efficient role of the unions that draws mainly on their capacity to internalize to the employer–employee relationships costs that would otherwise fall on society at large. 1. Introduction In this part of the volume, the overall theme is the policy dilemma created by the many different activities of trade union in the field of welfare provision, notably pension policies and unemployment protection. Throughout the following chapters, a tension emerges between the role of unions as insurance providers, as institutions that facilitate agreements between different parties, and as rent-seeking monopolists. By making use of an interdisciplinary approach, the analysis rationalizes a set of distinct features of the interaction between union activities and union structure on the one hand and welfare arrangements and welfare developments on the other. 2. Unions' Involvement in the Welfare State Shows that there are important correlations between the unions' strength and activities and their welfare outcomes. The chapter provides a taxonomy of the large differences across countries in unions' strength and social expenditure. The analysis distinguishes among four dimensions of union influence: (1) unions as political movements; (2) unions and self-administration in public schemes; (3) unions and private pensions; and (4) institutional participation and political veto points. 3. Unions and Pensions: Theory, Evidence, and Implications The relationship between union actions and welfare outcomes is developed, taking the provision of old-age insurance as a natural example. This chapter develops the economic theory of how unions go about setting policies on pensions; it presents empirical evidence of their impact on occupational pensions and policies on state pensions and early retirement options; and it examines how union activities depend on labour relations institutions. 4. Learning from Welfare Reforms: The Case of Public Pensions Provides a detailed account of the position of unions on pension reforms across Europe. This example is regarded as a major indicator establishing whether unions have a truly solidaristic approach in negotiating reforms or appear to be driven mainly by internal membership considerations and by a strong seniority bias. 5. Unions and Unemployment Insurance Differences in unionization rates across countries appear to be related to how unemployment insurance is organized in different countries. The chapter presents the involvement of unions in the provision of unemployment insurance, highlighting theoretical considerations, policy arguments, and empirical evidence in favour of a particular unemployment insurance arrangement known as the ‘Ghent regime’. 6. Conclusions Summarizes the main findings of this part of the report, stressing how the seniority bias in unions leads to economic outcomes that are more favourable to older workers. It analyses the ways in which unions can counteract this tendency and choose policies that benefit both young and older workers. Four final questions arise: (1) Do unions interact with the welfare state? How do they do it? (2) What explains union policies toward welfare outcomes? (3) Which institutional structure emphasizes unions' welfare-enhancing activities relative to unions' rent-seeking activities? (4) Can unions contribute to a reform of welfare systems