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

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

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

Active poly-GA vaccination prevents microglia activation and motor deficits in a <em>C9orf72</em> mouse model.

The C9orf72 repeat expansion is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). Non-canonical translation of the expanded repeat results in abundant poly-GA inclusion pathology throughout the CNS. (GA)(149)-CFP expression in mice triggers motor deficits and neuroinflammation. Since poly-GA is transmitted between cells, we investigated the therapeutic potential of anti-GA antibodies by vaccinating (GA)(149)-CFP mice. To overcome poor immunogenicity, we compared the antibody response of multivalent ovalbumin-(GA)(10) conjugates and pre-aggregated carrier-free (GA)(15). Only ovalbumin-(GA)(10) immunization induced a strong anti-GA response. The resulting antisera detected poly-GA aggregates in cell culture and patient tissue. Ovalbumin-(GA)(10) immunization largely rescued the motor function in (GA)(149)-CFP transgenic mice and reduced poly-GA inclusions. Transcriptome analysis showed less neuroinflammation in ovalbumin-(GA)(10)-immunized poly-GA mice, which was corroborated by semiquantitative and morphological analysis of microglia/macrophages. Moreover, cytoplasmic TDP-43 mislocalization and levels of the neurofilament light chain in the CSF were reduced, suggesting neuroaxonal damage is reduced. Our data suggest that immunotherapy may be a viable primary prevention strategy for ALS/FTD in C9orf72 mutation carriers

Poly-GP in cerebrospinal fluid links<em> C9orf72</em>-associated dipeptide repeat expression to the asymptomatic phase of ALS/FTD.

The C9orf72 GGGGCC repeat expansion is a major cause of amyotrophic lateral sclerosis and frontotemporal dementia (c9ALS/FTD). Non-conventional repeat translation results in five dipeptide repeat proteins (DPRs), but their clinical utility, overall significance, and temporal course in the pathogenesis of c9ALS/FTD are unclear, although animal models support a gain-of-function mechanism. Here, we established a poly-GP immunoassay from cerebrospinal fluid (CSF) to identify and characterize C9orf72 patients. Significant poly-GP levels were already detectable in asymptomatic C9orf72 mutation carriers compared to healthy controls and patients with other neurodegenerative diseases. The poly-GP levels in asymptomatic carriers were similar to symptomatic c9ALS/FTD cases. Poly-GP levels were not correlated with disease onset, clinical scores, and CSF levels of neurofilaments as a marker for axonal damage. Poly-GP determination in CSF revealed a C9orf72 mutation carrier in our cohort and may thus be used as a diagnostic marker in addition to genetic testing to screen patients. Presymptomatic expression of poly-GP and likely other DPR species may contribute to disease onset and thus represents an alluring therapeutic target

Spinal poly-GA inclusions in a <em>C9orf72 </em>mouse model trigger motor deficits and inflammation without neuron loss.

Translation of the expanded (ggggcc)n repeat in C9orf72 patients with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) causes abundant poly-GA inclusions. To elucidate their role in pathogenesis, we generated transgenic mice expressing codon-modified (GA)149 conjugated with cyan fluorescent protein (CFP). Transgenic mice progressively developed poly-GA inclusions predominantly in motoneurons and interneurons of the spinal cord and brain stem and in deep cerebellar nuclei. Poly-GA co-aggregated with p62, Rad23b and the newly identified Mlf2, in both mouse and patient samples. Consistent with the expression pattern, 4-month-old transgenic mice showed abnormal gait and progressive balance impairment, but showed normal hippocampus-dependent learning and memory. Apart from microglia activation we detected phosphorylated TDP-43 but no neuronal loss. Thus, poly-GA triggers behavioral deficits through inflammation and protein sequestration that likely contribute to the prodromal symptoms and disease progression of C9orf72 patients

Policy concertation in Europe: explaining government’s choice

This article focuses on the European governments' decision to involve unions and employers in the design and implementation of public policy. Based on new measures of the phenomenon, the authors argue that between 1974 and 2003, no convergence on a pluralist model of policy formation is visible. They then use these measures to identify and analyze the clearest cases of adoption or demise of concertation, namely, the contrasting responses of the British and Irish governments to wage policy and of the Austrian and Italian governments to pension reform. They argue that governments are willing to share their policy-making prerogatives when they are politically weak and when unions, while still representing a credible threat to policy implementation, have been declining in the recent past. A combination of partisanship and policy learning reinforces the push for change