Amyotrophic lateral sclerosis is a systemic disease: peripheral contributions to inflammation-mediated neurodegeneration

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14 Scopus citations


Purpose of review Neuroinflammation is an important mediator of the pathogenesis of disease in amyotrophic lateral sclerosis (ALS). Genetic mutations such as C9orf72 have begun to define the numerous cell autonomous pathways that initiate motor neuron injury. Yet, it is the signalling to surrounding glia and peripherally derived immune cells that initiates the noncell autonomous inflammatory process and promotes self-propagating motor neuron cell death. The purpose of this review is to explore the systemic immune/inflammatory contributions to the pathogenesis of ALS: what are the peripheral pro-inflammatory signatures, what initiates their presence and do they represent potential therapeutic targets. Recent findings In ALS, motor neuron cell death is initiated by multiple cell autonomous pathways leading to misfolded proteins, oxidative stress, altered mitochondria, impaired autophagy and altered RNA metabolism, which collectively promote noncell autonomous inflammatory reactivity. The resulting disease is characterized by activated microglia and astrocytes as well as peripherally derived pro-inflammatory innate and adaptive immune cells. In this unrelenting disorder, circulating blood monocytes and natural killer cells are proinflammatory. Furthermore, regulatory T lymphocytes are dysfunctional, and pro-inflammatory cytokines and acute phase proteins are elevated. Summary The collective dysregulation of cells and cytokines in patients with ALS accurately reflect increased disease burdens, more rapid progression rates and reduced survival times, reinforcing the concept of ALS as a disorder with extensive systemic pro-inflammatory responses. These increased systemic pro-inflammatory immune constituents provide potentially meaningful therapeutic targets.

Original languageEnglish (US)
Pages (from-to)765-772
Number of pages8
JournalCurrent opinion in neurology
Issue number5
StatePublished - Oct 1 2021


  • Amyotrophic lateral sclerosis
  • Neuroinflammation
  • Systemic inflammation

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology


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