Systematic interaction network filtering identifies CRMP1 as a novel suppressor of huntingtin misfolding and neurotoxicity

Abstract

Assemblies of huntingtin (HTT) fragments with expanded polyglutamine (polyQ) tracts are a pathological hallmark of Huntington's disease (HD). The molecular mechanisms by which these structures are formed and cause neuronal dysfunction and toxicity are poorly understood. Here, we utilized available gene expression data sets of selected brain regions of HD patients and controls for systematic interaction network filtering in order to predict disease-relevant, brain region-specific HTT interaction partners. Starting from a large protein-protein interaction (PPI) data set, a step-by-step computational filtering strategy facilitated the generation of a focused PPI network that directly or indirectly connects 13 proteins potentially dysregulated in HD with the disease protein HTT. This network enabled the discovery of the neuron-specific protein CRMP1 that targets aggregation-prone, N-terminal HTT fragments and suppresses their spontaneous self-assembly into proteotoxic structures in various models of HD. Experimental validation indicates that our network filtering procedure provides a simple but powerful strategy to identify disease-relevant proteins that influence misfolding and aggregation of polyQ disease proteins.

Proenkephalin Decreases in Cerebrospinal Fluid with Symptom Progression of Huntington's Disease

“…In plasma from HD patients, brain‐derived 24‐OH cholesterol deficiency has been found, 40 and impaired cholesterol synthesis in the CNS has also been observed in a HD mouse model 41 . Further, evidence suggests that polyglutamine toxicity may be countered by high mobility group box proteins HMGB1/2 42 —homologs of the HMGA1, 43 a pathway that was also disrupted in our study.…”

Spatiotemporal Proteomic Profiling of Huntington’s Disease Inclusions Reveals Widespread Loss of Protein Function

“…All five members of the collapsin response mediator protein (Crmp) family, also known as dihydropyrimidinase-related proteins (Dpysl), were also enriched ( Figure 5 B). A study identified Crmp1 as a suppressor of huntingtin toxicity ( Stroedicke et al., 2015 ). Apart from confirming these known aggregate constituents, our data provide a large number of new proteins with potential links to HD ( Table S3 A).…”

The unfolded protein response and its potential role in Huntington's disease elucidated by a systems biology approach

“…In addition, we extracted genes, whose corresponding proteins were reported to be physically associated with HTT, from the HDNetDB database. We recently demonstrated that HTT interactors tend to be enriched in proteins that influence the toxicity of mHTT, and provide favourable candidates for the identification of molecular modifiers of HD 74 .…”