Dysregulated molecular pathways in amyotrophic lateral sclerosis-frontotemporal dementia spectrum disorder

Abstract

Frontotemporal dementia (FTD), the second most common form of dementia in people under 65 years of age, is characterized by progressive atrophy of the frontal and/or temporal lobes. FTD overlaps extensively with the motor neuron disease amyotrophic lateral sclerosis (ALS), especially at the genetic level. Both FTD and ALS can be caused by many mutations in the same set of genes; the most prevalent of these mutations is a GGGGCC repeat expansion in the first intron of C9ORF72 As shown by recent intensive studies, some key cellular pathways are dysregulated in the ALS-FTD spectrum disorder, including autophagy, nucleocytoplasmic transport, DNA damage repair, pre-mRNA splicing, stress granule dynamics, and others. These exciting advances reveal the complexity of the pathogenic mechanisms of FTD and ALS and suggest promising molecular targets for future therapeutic interventions in these devastating disorders.

Keywords: ALS; FTD; FUS; C9ORF72; TDP‐43.

Figure 1. Genes with genetic mutations that cause both FTD and ALS

These genes are listed chronologically by year of discovery of their involvement in FTD and ALS. Two major pathological proteins in both FTD and ALS—TDP‐43 (encoded by the TARDBP gene) and FUS—are also listed here.

Figure 2. The C9ORF72 locus and its downstream RNA and protein products

The three C9ORF72 variants are named based on the latest information in the NCBI database. Expanded G₄C₂ repeat‐containing intron and G₂C₄ repeat‐containing RNA generated through an unknown mechanism can form either RNA foci or be translated into DPR proteins. Unspliced pre‐mRNA may also serve as the template for DPR production (not shown). C9ORF72 isoform a contains a DENN domain and interacts with SMCR8 in autophagy.

Figure 3. Nucleocytoplasmic transport defects in different neurodegenerative diseases

In C9ORF72‐related FTD/ALS, expanded G₄C₂ repeats bind to RanGAP and disrupt the Ran gradient; poly(PR) interacts with the FG repeats of nuclear pore proteins; poly(GR) binds to importin; and poly(GA) aggregates sequester RanGAP and HR23. Cytoplasmic and nuclear aggregates formed by TDP‐43 or mutant huntingtin (mHTT) sequester some NPC components and factors important for nucleocytoplasmic transport.

Figure 4. The roles of different FTD/ALS disease proteins in SG formation

Upper left: An artificial sequence is presented to illustrate the amino acid composition of LCDs. Upper right: A schematic representation of liquid–liquid phase separation in vitro that can be influenced by salt concentrations or RNA concentrations or genetic mutations. Center: TDP‐43 aggregates or inhibition of general translation by arginine‐rich DPR proteins can lead to elF2α phosphorylation which promotes SG formation. Mutant proteins in FTD/ALS such as FUS or ataxin‐2 promote the formation of irreversible aggregates and thereby prevent the dissociation of SGs. Lower left: A schematic representation of some individual components of SGs. LCD: LCD‐containing RBPs. Lower right: A schematic representation of an SG with a densely packed core.