Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43 ribonucleoprotein condensates disrupting mRNA transport and local translation in neurons.

Altered RNA metabolism and misregulation of transactive response DNA-binding protein of 43 kDa (TDP-43), an essential RNA-binding protein (RBP), define amyotrophic lateral sclerosis (ALS). Intermediate-length polyglutamine (polyQ) expansions of Ataxin-2, a like-Sm (LSm) RBP, are associated with increased risk for ALS, but the underlying biological mechanisms remain unknown. Here, we studied the spatiotemporal dynamics and mRNA regulatory functions of TDP-43 and Ataxin-2 ribonucleoprotein (RNP) condensates in rodent (rat) primary cortical neurons and mouse motor neuron axons in vivo.

Phase separation and pathologic transitions of RNP condensates in neurons: implications for amyotrophic lateral sclerosis, frontotemporal dementia and other neurodegenerative disorders.

Liquid-liquid phase separation results in the formation of dynamic biomolecular condensates, also known as membrane-less organelles, that allow for the assembly of functional compartments and higher order structures within cells. Multivalent, reversible interactions between RNA-binding proteins (RBPs), including FUS, TDP-43, and hnRNPA1, and/or RNA (e.g.

Ataxin-2 polyglutamine expansions aberrantly sequester TDP-43, drive ribonucleoprotein condensate transport dysfunction and suppress local translation.

Altered RNA metabolism is a common pathogenic mechanism linked to familial and sporadic Amyotrophic lateral sclerosis (ALS). ALS is characterized by mislocalization and aggregation of TDP-43, an RNA-binding protein (RBP) with multiple roles in post-transcriptional RNA processing. Recent studies have identified genetic interactions between TDP-43 and Ataxin-2, a polyglutamine (polyQ) RBP in which intermediate length polyQ expansions confer increased ALS risk.

Sequence Determinants of TDP-43 Ribonucleoprotein Condensate Formation and Axonal Transport in Neurons.

Mutations in TDP-43, a RNA-binding protein with multiple functions in RNA metabolism, cause amyotrophic lateral sclerosis (ALS), but it is uncertain how defects in RNA biology trigger motor neuron degeneration. TDP-43 is a major constituent of ribonucleoprotein (RNP) granules, phase separated biomolecular condensates that regulate RNA splicing, mRNA transport, and translation. ALS-associated TDP-43 mutations, most of which are found in the low complexity domain, promote aberrant liquid to solid phase transitions and impair the dynamic liquid-like properties and motility of RNP transport granules in neurons.

14-3-3γ-Mediated transport of plakoglobin to the cell border is required for the initiation of desmosome assembly in vitro and in vivo.

The regulation of cell-cell adhesion is important for the processes of tissue formation and morphogenesis. Here, we report that loss of 14-3-3γ leads to a decrease in cell-cell adhesion and a defect in the transport of plakoglobin and other desmosomal proteins to the cell border in HCT116 cells and cells of the mouse testis. 14-3-3γ binds to plakoglobin in a PKCμ-dependent fashion, resulting in microtubule-dependent transport of plakoglobin to cell borders.