TDP-43 neurotoxicity and protein aggregation modulated by heat shock factor and insulin/IGF-1 signaling

Abstract

TAR DNA-binding protein 43 (TDP-43) plays a key role in the neurodegenerative diseases including amyotrophic lateral sclerosis and frontotemporal lobar degeneration. The nature of the TDP-43-mediated neurotoxicity associated with these diseases is not yet understood. Here, we have established transgenic Caenorhabditis elegans models that express human TDP-43 variants in the nervous system, including the full-length wild-type (WT) and mutant proteins and a pathologic C-terminal fragment. The C. elegans models developed severe locomotor defects associated with the aggregation of TDP-43 in neurons. In comparison to parallel Cu/Zn superoxide dismutase worm models, transgenic full-length TDP-43, including the WT protein, was highly neurotoxic. In addition, TDP-43 demonstrated an unusually high tendency to aggregate, a property intrinsic to the WT protein. The C-terminal 25 kDa fragment of TDP-43 was unstable but remarkably aggregation-prone. Distinct disulfide-linked TDP-43 dimers and oligomers were detected. In C. elegans, the neurotoxicity and the protein aggregation of TDP-43 were regulated by environmental temperature and heat shock transcriptional factor 1, indicating that a deficiency in protein quality control is a risk factor for TDP-43 proteinopathy. Furthermore, the neurotoxicity and the protein aggregation of TDP-43 can be significantly attenuated by a deficiency in the insulin/insulin-like growth factor 1 (IGF-1) signaling in C. elegans and mammalian cells. These results suggest that protein misfolding underlies the aging-dependent neurodegeneration associated with TDP-43 and that the insulin/IGF-1 signaling may be a target for therapies.

Aberrant Assembly of RNA Recognition Motif 1 Links to Pathogenic Conversion of TAR DNA-binding Protein of 43 kDa (TDP-43)

“…The cell death appeared non-apoptotic, because we observed no activation of caspase-3/7 during the 48-h cell culture (not shown). It was reported that C-terminal 25-or 35-kDa fragments, not containing RRM1, replicate TDP-43 proteinopathy in cells (28) and in vivo models (43,44). However, we found no relationship between the amount of these fragments (Fig.…”

“…TAR DNA-binding protein of 43 kDa (TDP- 43) 3 is a DNAand RNA-binding nuclear protein that has been identified as a core component of ubiquitinated inclusions in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS) (1,2). Accumulating evidence suggests that TDP-43 proteinopathy mediates motor neuron degeneration in familial ALS caused by diverse genetic defects in ubiquilin 2, profilin 1, optineurin, valosin-containing protein, and C9ORF72 (reviewed in Ref.…”

mRNP granules

“…147 In addition, pathogenic forms of TDP-43 expressed in C. elegans or Drosophila show slower exchange rates from aggregates or neuronal granules by FRAP. 127,148 Several reasons have been proposed as to why persistent stress granules or related mRNP aggregates could be toxic to cells. 136,144 Sequestration of protein factors in granules could lead to a reduced ability of granules to appropriately remodel mRNPs, and may limit the available pool of a protein that also functions elsewhere in the cell.…”

A Neuronal GPCR is Critical for the Induction of the Heat Shock Response in the NematodeC. elegans

“…Therefore, IIS reduction elevates stress resistance by hyperactivating DAF-16 and HSF-1 (Lithgow et al, 1995;Honda and Honda, 1999). This manipulation also extends lifespan and protects from proteotoxicity Morley and Morimoto, 2004;Cohen et al, 2006;Teixeira-Castro et al, 2011;Zhang et al, 2011), raising the question of whether these functions are mechanistically linked.…”