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.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1125-6) contains supplementary material, which is available to authorized users.

Beneficial effects of rapamycin in a Drosophila model for hereditary spastic paraplegia

“…Polyubiquitin aggregate accumulation can occur as a result of the expression of mutant misfolding proteins (Blokhuis et al, 2013), but this is unlikely to be the cause of the aggregate accumulation we observe because the muscle remains genetically wild-type when atl is knocked down in neurons. Polyubiquitin aggregate accumulation can also be caused by autophagy inhibition (Rubinsztein, 2006).…”

“…In addition to promoting damage, however, ROS can act as a signaling molecule. Reactive oxygen increases expression of the anti-oxidants Catalase (Cat) and SOD1 by activating the MAP kinase JNK, which in turn phosphorylates and activates the transcription factor Foxo, which is a direct transcriptional activator of Cat and SOD1 (Essers et al, 2004;van den Berg et al, 2013;Wang et al, 2005). Thus, we asked whether atl loss activated muscle JNK and Foxo.…”

“…These aggregates can be generated through expression of mutant misfolding proteins (Blokhuis et al, 2013), as is the case for the SOD1 G85R mutation that is causal for amyotrophic lateral sclerosis (ALS; Bruijn et al, 1998). However, protein aggregates can accumulate even in cells that do not express misfolding mutants.…”

ALS mutations in TLS/FUS disrupt target gene expression

“…We suggest that both of these effects, like the splicing defect, result from the mutant FUS-containing aggregates but here are due to the physical sequestration of MECP2 mRNA in a manner that blocks both mRNA turnover and translation. It is important to note that cytoplasmic aggregates are a common feature of ALS (Blokhuis et al 2013;Li et al 2013), yet it has not been clear what function, if any, these aggregates play in disease pathogenesis. Our results thus demonstrate that such aggregates can indeed play a critical function, which is disrupting expression of specific genes.…”

Energy metabolism in amyotrophic lateral sclerosis: assessment of body composition and energy expenditure

“…Proposed pathogenic mechanisms include mitochondrial dysfunction (Hervias et al, 2006, Muyderman andChen, 2014), glutamate excitotoxicity (Heath andShaw, 2002, Vucic andKiernan, 2006) and abnormal protein aggregation (Mackenzie et al, 2007, Blokhuis et al, 2013. These mechanisms are summarized in Figure 1.1.…”