Protein aggregation in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the aggregation of ubiquitinated proteins in affected motor neurons. Recent studies have identified several new molecular constituents of ALS-linked cellular aggregates, including FUS, TDP-43, OPTN, UBQLN2 and the translational product of intronic repeats in the gene C9ORF72. Mutations in the genes encoding these proteins are found in a subgroup of ALS patients and segregate with disease in familial cases, indicating a causal relationship with disease pathogenesis. Furthermore, these proteins are often detected in aggregates of non-mutation carriers and those observed in other neurodegenerative disorders, supporting a widespread role in neuronal degeneration. The molecular characteristics and distribution of different types of protein aggregates in ALS can be linked to specific genetic alterations and shows a remarkable overlap hinting at a convergence of underlying cellular processes and pathological effects. Thus far, self-aggregating properties of prion-like domains, altered RNA granule formation and dysfunction of the protein quality control system have been suggested to contribute to protein aggregation in ALS. The precise pathological effects of protein aggregation remain largely unknown, but experimental evidence hints at both gain- and loss-of-function mechanisms. Here, we discuss recent advances in our understanding of the molecular make-up, formation, and mechanism-of-action of protein aggregates in ALS. Further insight into protein aggregation will not only deepen our understanding of ALS pathogenesis but also may provide novel avenues for therapeutic intervention.

Fig. 1

Schematic representation of the domain organization of TDP-43, FUS, ATXN2, OPTN and UBQLN2. Different protein domains are indicated in different colors (see legend). The location of ALS-associated genetic alterations is depicted by sticks (mutations) or arrowheads (repeats). For C9ORF72 intronic and exonic regions are depicted; an intronic hexanucleotide repeat is causative of ALS/FTD (arrowhead). Boxes show a selection of relevant interactors for each of the depicted proteins

Fig. 2

Cellular mechanisms linked to protein aggregation in ALS. ALS-associated mutations result in cytoplasmic mislocalization or increased aggregation tendency thereby increasing the risk for aberrant aggregation. Proteins with domains of low complexity (prion-like domains) such as FUS, TDP-43 and HNRNPA1 are though to be intrinsically aggregation prone. Many of these proteins participate in RNA granule formation. ALS-associated mutants alter RNA granule formation, thereby interfering with the local translation of RNA. Moreover, sequestration of ALS-associated proteins and their interactors into cytoplasmic aggregates may result in a loss of function. Protein degradation by the UPS and autophagy is essential for the clearance of ubiquitinated proteins. Dysfunction of these systems, as has been suggested for mutant UBQLN2, OPTN and VCP, can lead to proteins deposits