Cellular clearance of circulating transthyretin decreases cell-nonautonomous proteotoxicity in Caenorhabditis elegans

Abstract

Cell-autonomous and cell-nonautonomous mechanisms of neurodegeneration appear to occur in the proteinopathies, including Alzheimer's and Parkinson's diseases. However, how neuronal toxicity is generated from misfolding-prone proteins secreted by nonneuronal tissues and whether modulating protein aggregate levels at distal locales affects the degeneration of postmitotic neurons remains unknown. We generated and characterized animal models of the transthyretin (TTR) amyloidoses that faithfully recapitulate cell-nonautonomous neuronal proteotoxicity by expressing human TTR in the muscle. We identified sensory neurons with affected morphological and behavioral nociception-sensing impairments. Nonnative TTR oligomer load and neurotoxicity increased following inhibition of TTR degradation in distal macrophage-like nonaffected cells. Moreover, reducing TTR levels by RNAi or by kinetically stabilizing natively folded TTR pharmacologically decreased TTR aggregate load and attenuated neuronal dysfunction. These findings reveal a critical role for modulation of aggregation-prone degradation that directly affects postmitotic tissue degeneration observed in the proteinopathies.

Development of transgenic Caenorhabditis elegans expressing human transthyretin as a model for drug screening

“…Interestingly, CMPD5, a TTR-selective fluorogenic dye, binds the TTR tetramer in the body cavity and functions as a tetramer stabilizer. Therefore, CMPD5 feeding rescued the locomotion defect caused by TTR V30M 46 . On the other hand, it can be reasonably assumed that β-cyclodextrin does not inhibit TTR misfolding sufficiently because of its poor intestinal adsorption 47 .…”

“…Very recently, Madhivanan et al . reported that non-tagged, secreted TTR V30M can form non-native oligomers in the body cavity, causing defects in neuronal morphology and locomotion 46 . Interestingly, CMPD5, a TTR-selective fluorogenic dye, binds the TTR tetramer in the body cavity and functions as a tetramer stabilizer.…”

Transthyretin Amyloidosis: Update on the Clinical Spectrum, Pathogenesis, and Disease-Modifying Therapies

“…To support this view, studies using schwannoma or neuroblastoma cell lines demonstrated the toxic effects of nonfibrillar TTR [ 47 , 57 – 59 ]. Animal models using Caenorhabditis elegans or Drosophila also demonstrated the neurotoxicity of TTR despite the absence of fibrillar amyloid deposition [ 59 , 60 ]. As the amount of endoneurial amyloid deposition is smaller relative to the extent of nerve fiber loss in patients with late-onset Val30Met ATTR amyloidosis compared to patients with early-onset Val30Met ATTR amyloidosis [ 21 ], the toxicity of nonfibrillar TTR may participate in the process of neurodegeneration in some of the patients with ATTR amyloidosis, such as those with late-onset Val30Met ATTR amyloidosis.…”

C. elegans Models to Study the Propagation of Prions and Prion-Like Proteins

“…In these diseases, the native TTR tetramer, which usually circulates in the blood and central nervous system fluid, is destabilized by particular mutations, and the monomers misfold and form amyloids, which are systemically deposited and mainly damage cardiac tissue and neurons [ 140 ]. The expression of disease-related TTR mutants in C. elegans muscle cells not only led to cell autonomous toxicity but also affected multiple neurons, resulting in dendritic abnormalities of polymodal nociceptive FLP neurons, and a shortening of mitochondria in mechanosensory neurons [ 67 ]. Analogous observations were made in Drosophila , where the transmission of pathological HTT Exon1-12-polyQ138 induced non-cell autonomous cell death [ 96 ] and widespread apoptosis activation [ 141 ] in the brain, although its expression was restricted to olfactory receptor neurons.…”