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Final Report Summary - TREATPOLYQ (TreatPolyQ – Industrial Academic Initial Training Network towards treatment of Polyglutamine Diseases.)

Protein aggregation is a hallmark of many late onset neurodegenerative diseases including Parkinson’s and Alzheimer’s Disease, amylotrophic lateral sclerosis, prion diseases as well as the group of polyglutamine diseases (polyQ). Main representatives of the latter are Huntington’s Disease (HD) and Spinocerebellar Ataxia type 3 (SCA3). TreatPolyQ not only focuses on one special aspect of an individual disease but spans several important disease-associated mechanisms, as well as promising treatment strategies for both HD and SCA3.

TreatPolyQ partners have established a lively network and profit from the exchange of both knowledge and research capabilities and resources. All fellows were integrated in the training program of TreatPolyQ – both local and network-wide training measures. The results of TreatPolyQ were appreciated in a final meeting open to the public. The TreatPolyQ website ( was established to raise the public awareness of the project. It also contains internal pages that are used as a teaching and reference tool for the fellows.

Intracellular localisation and protein transport: Nuclear localisation of Ataxin 3 is of critical importance for the pathogenesis and a promising target for pharmaceutical interventions. Research within TreatPolyQ identified highly interesting proteins involved in the transport process. Transport proteins are involved in the formation of the intranuclear aggregates, typically observed in SCA3 patients and modulation of these transport proteins alleviated the phenotype induced by expanded ataxin-3. Huntingtin (HTT) itself influences the vesicular transport of neurotrophic factors via phosphorylation. This function is disturbed in HD, leading to neuronal death, but this deleterious effect might be rescued by phosphorylation of the protein. TreatPolyQ researchers engage in unravelling the relation between specific conformations of HTT and protein complexes that should lead to a better understanding of the role of the HTT protein in health and disease.

Protein aggregation and degradation: As protein aggregation is a hallmark of PolyQ disorders (and also other neurodegenerative diseases), it is crucial to understand why polyQ-containing proteins aggregate, by which mechanisms they are degraded and how they can be specifically targeted for protein degradation. Depending on the label with ubiquitin, proteins may be degraded either via proteasomes or via macroautophagy. Only the latter pathway is able to degrade aggregates. Therefore, we designed a specific engineered ubiquitin-ligase that is capable of inducing ubiqitin-selective autophagy in cell-lines and thereby reduces toxicity of polyQ proteins. We identified peptides that may be used to interfere with huntingtin exon 1 assembly into fibrils and demonstrated that fibrillar huntingtin exon 1 is taken up by cells by endocytosis and directed to the lysosomal compartment. Autophagy upregulation might also protect against HD. Two genes have been identified that regulate autophagy of insoluble aggregates of mutant protein. Long-term imaging and and activity recording were used to reveal the functional link between early onset synaptic dysfunction and global deficits in proteasomal degradation associated with HD pathology. Preliminary results indicate major synaptic changes that occur as a result of mutant huntingtin (mHTT) expression. Among them are higher global activity of the network and abnormal enlargement of the synapses.

Experimental therapeutics: To date, there is no causal treatment available for PolyQ disorders, therefore there is an urgent need to develop novel therapeutic strategies. These might be achieved via modification of gene expression patterns or restoration of the disturbed protein homeostasis. Furthermore, we aim to establish bioassays to identify the modulators of polyQ-pathogenesis. We have developed several novel immunological tools and scalable assays that are able to quantitatively measure HTT protein levels (full length HTT, fragmented HTT) and HTT interaction in cellular models as well as in body fluids, and we have successfully identified enzymes that are able to modify post translational modifications of HTT in these models. We identified enzymes that are responsible for maintaining the correct labelling of HTT and Ataxin 3 for degradation. Further demonstration that inhibition of these enzymes leads to increased clearance of the disease causing proteins (disappearance of pathology) will enable us to develop enzyme inhibitors with the potential to treat HD and SCA3. With the development of new fly models and innovative screening strategies, we could identify new putative therapeutic targets and several promising compounds to treat SCA3 and HD. Additional studies in fly and mammals are required to fully validate these molecules for therapeutic purposes. Furthermore, modifications of disease-associated mRNA showed neuroprotective effects in SCA 3 mouse models. In an HD mouse model, we identified enzymes capable to restore the chaperone-mediated autophagy, that is reduced in HD. The therapeutic impact of this finding is still under investigation. To prove the feasibility of a small molecule therapeutic for HD, we developed various in vitro assays for the screening of potential small molecules as inhibitors for mutant HTT aggregation processes. A compound was identified to disassociate preformed HTT aggregates and showed inhibition of protein aggregation processes in vitro.

TreatPolyQ produced a group of well-trained young scientists for the future of this important field, reflected in the delivery of high-ranking publications and PhD theses. Together with the inter-sector working experience with both academic and industrial partners, plus a broad-ranging scientific training enabling “thinking outside the box” and complementary skill training, the fellows are equipped to meet the demands of the European employment market.
Regarding the scientific results, we succeeded in deciphering important mechanisms associated with PolyQ disease, as well as in identifying promising treatment approaches for HD and SCA3.

In addition to educating fellows for the European employment market, the TreatPolyQ outreach program should also be mentioned as a measure that achieved impact on society. The scientific results obtained significantly advanced the basic understanding of polyQ disease etiology, on which the development of new therapeutic approaches and biomarkers can be based. Long-term these results will clearly impact patients, care takers and patients families significantly, but are likely need another 10 years or so to reach patients in terms of new treatment paradigms.

University of Tuebingen
Institute of Medical Genetics and Applied Genomics, Research Management
Calwerstrasse 7
72076 Tuebingen
Phone +49 7071 29 72191
Fax +49 7071 29 25061

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