Linking hnRNP Function to ALS and FTD Pathology

Abstract

Following years of rapid progress identifying the genetic underpinnings of amyotrophic lateral sclerosis (ALS) and related diseases such as frontotemporal dementia (FTD), remarkable consistencies have emerged pointing to perturbed biology of heterogeneous nuclear ribonucleoproteins (hnRNPs) as a central driver of pathobiology. To varying extents these RNA-binding proteins are deposited in pathological inclusions in affected tissues in ALS and FTD. Moreover, mutations in hnRNPs account for a significant number of familial cases of ALS and FTD. Here we review the normal function and potential pathogenic contribution of TDP-43, FUS, hnRNP A1, hnRNP A2B1, MATR3, and TIA1 to disease. We highlight recent evidence linking the low complexity sequence domains (LCDs) of these hnRNPs to the formation of membraneless organelles and discuss how alterations in the dynamics of these organelles could contribute to disease. In particular, we discuss the various roles of disease-associated hnRNPs in stress granule assembly and disassembly, and examine the emerging hypothesis that disease-causing mutations in these proteins lead to accumulation of persistent stress granules.

Keywords: amyotrophic lateral sclerosis; frontotemporal dementia; hnRNPs; membraneless organelles; stress granules.

Figure 1

Mutations that cause ALS and FTD cluster in the LCD of hnRNPs and/or disrupt nuclear localization. TDP-43, FUS, hnRNP A1, hnRNP A2B1, MATR3, and TIA1 are ubiquitously expressed hnRNPs that are similar in domain structure and function, each containing at least one RRM and LCD. The LCD region of all hnRNPs is well established with the exception of MATR3, for which PONDR score analysis (http://www.pondr.com/) was used to identify the disordered LCD regions. Mutations identified in patients with ALS, FTD, and/or MSP are depicted as red circles. Mutations in TDP-43, FUS, hnRNP A1, hnRNP A2B1, and TIA1 primarily cluster in the LCD region, whereas mutations in MATR3 are less concentrated in a single region. Several mutations are also found in the NLS of FUS and one in the NLS of TDP-43, causing them to mislocalize to the cytoplasm. MATR3 contains mutations in both the NES and NLS, although further studies are necessary to confirm their effects on MATR3 localization. RRM, RNA recognition motif; LCD, low-complexity domain; NLS, nuclear localization signal; NES, nuclear export signal; RGG, Arg-Gly-Gly box; ZnF, zinc finger; PY-NLS, proline-tyrosine NLS; PRI, polypyrimidine tract binding (PTB)-RRM interaction domain.

Figure 2

ALS mutations alter the dynamics and function of membraneless organelles. RNA-binding proteins associate with mRNA, forming mRNPs that are transported to the cytosol. The hnRNPs discussed in this review contain LCDs that mediate phase separation, contributing to the assembly/disassembly, dynamics, and liquid properties of membraneless organelles such as stress granules. Stress granules that begin forming aggregates and are no longer capable of being disassembled by liquid-liquid phase separation mechanisms are cleared by autophagy/granulophagy. Disease-causing mutations can trigger the assembly of aberrant or persistent membraneless organelles in which the high concentration and close interactions of the LCDs over time may promote the transition of aggregation-prone proteins (e.g., TDP-43, FUS) to pathogenic amyloid fibrils. mRNP, messenger ribonucleoprotein particle; LCDs, low complexity domains.