WP 10 - 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 politics of pensions in European social insurance countries

"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." [Autorenreferat]"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." [author's abstract

Loss of TMEM106B potentiates lysosomal and FTLD-like pathology in progranulin-deficient mice

Single nucleotide polymorphisms (SNPs) in TMEM106B encoding the lysosomal type II transmembrane protein 106B increase the risk for frontotemporal lobar degeneration (FTLD) of GRN (progranulin gene) mutation carriers. Currently, it is unclear if progranulin (PGRN) and TMEM106B are synergistically linked and if a gain or a loss of function of TMEM106B is responsible for the increased disease risk of patients with GRN haploinsufficiency. We therefore compare behavioral abnormalities, gene expression patterns, lysosomal activity, and TDP-43 pathology in single and double knockout animals. Grn-/- /Tmem106b-/- mice show a strongly reduced life span and massive motor deficits. Gene expression analysis reveals an upregulation of molecular signature characteristic for disease-associated microglia and autophagy. Dysregulation of maturation of lysosomal proteins as well as an accumulation of ubiquitinated proteins and widespread p62 deposition suggest that proteostasis is impaired. Moreover, while single Grn-/- knockouts only occasionally show TDP-43 pathology, the double knockout mice exhibit deposition of phosphorylated TDP-43. Thus, a loss of function of TMEM106B may enhance the risk for GRN-associated FTLD by reduced protein turnover in the lysosomal/autophagic system

Active poly-GA vaccination prevents microglia activation and motor deficits in a C9orf72 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

Cytoplasmic poly-GA aggregates impair nuclear import of TDP-43 in C9orf72 ALS/FTLD

A repeat expansion in the non-coding region of C9orf72 gene is the most common mutation causing frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Sense and antisense transcripts are translated into aggregating dipeptide repeat (DPR) proteins in all reading frames (poly-GA,-GP,-GR,-PA and -PR) through an unconventional mechanism. How these changes contribute to cytoplasmic mislocalization and aggregation of TDP-43 and thereby ultimately leading to neuron loss remains unclear. The repeat RNA itself and poly-GR/PR have been linked to impaired nucleocytoplasmic transport. Here, we show that compact cytoplasmic poly-GA aggregates impair nuclear import of a reporter containing the TDP-43 nuclear localization (NLS) signal. However, a reporter containing a non-classical PY-NLS was not affected. Moreover, poly-GA expression prevents TNF alpha induced nuclear translocation of p65 suggesting that poly-GA predominantly impairs theimportin-alpha/beta-dependent pathway. In neurons, prolonged poly-GA expression induces partial mislocalization of TDP-43 into cytoplasmic granules. Rerouting poly-GA to the nucleus prevented TDP-43 mislocalization, suggesting a cytoplasmic mechanism. In rescue experiments, expression of importin-alpha (KPNA3, KPNA4) or nucleoporins (NUP54, NUP62) restores the nuclear localization of the TDP reporter. Taken together, inhibition of nuclear import of TDP-43 by cytoplasmic poly-GA inclusions causally links the two main aggregating proteins in C9orf72 ALS/FTLD pathogenesis

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