Protein aggregation in amyotrophic lateral sclerosis

Anna M. Blokhuis, Ewout J. N. Groen, Max Koppers, Leonard H. van den Berg, R. Jeroen Pasterkamp*

*Corresponding author for this work

Research output: Contribution to journalLiterature reviewpeer-review

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.

Original languageEnglish
Pages (from-to)777-794
Number of pages18
JournalActa Neuropathologica
Volume125
Issue number6
DOIs
Publication statusPublished - Jun 2013

Keywords

  • Amyotrophic lateral sclerosis (ALS)
  • Aggregation
  • Protein degradation
  • Motor neuron
  • RNA granule
  • FRONTOTEMPORAL LOBAR DEGENERATION
  • DNA-BINDING PROTEIN
  • HEXANUCLEOTIDE REPEAT EXPANSIONS
  • LENGTH POLYGLUTAMINE EXPANSIONS
  • SPINAL MUSCULAR-ATROPHY
  • RNA-PROCESSING PROTEIN
  • TDP-43 TRANSGENIC MICE
  • C-TERMINAL FRAGMENTS
  • NEURON DISEASES ALS
  • PRION-LIKE DOMAINS

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