Cell to cell spreading of misfolded proteins as a therapeutic target in motor neuron disease

Livia Pasquali, Paola Lenzi, Francesca Biagioni, Gabriele Siciliano, Francesco Fornai

Research output: Contribution to journalArticlepeer-review


Despite a number of genetic mutations and molecular mechanisms are recognized to participate in amyotrophic lateral sclerosis (ALS), such a devastating neurological disorder still lacks a substantial cure. The present manuscript rather than a general overview of potential therapeutic approaches focuses on novel research findings detailing novel molecular mechanisms which appear to be promising for developing future ALS therapeutics. A special emphasis is given to the abnormal autophagy status and to those autophagy substrates which aggregate in the form of misfolded proteins. In fact, as reviewed in the first part of the manuscript, altered autophagy pathway is present in most genetic mutations responsible for familial ALS. These mutations impair clearance of autophagy substrates, which determines accumulation of giant altered mitochondria and misfolded proteins. Therefore, a considerable piece of the review is dedicated to unconventional processing of misfolded proteins leading to unconventional protein secretions which may underlie a prionoid celltocell spreading of ALS neuropathology. The intimate mechanisms regulating these steps are analyzed in order to comprehend which potential therapeutic targets might be considered in future studies. At the same time, negative findings concerning recent trials are explained in light of novel disease mechanisms. In the final part of the review the replacement therapy with focal stem cells implantation is discussed in relationship with toxic mechanisms operating in the intercellular space of the spinal cord and motor-related areas.

Original languageEnglish
Pages (from-to)3508-3534
Number of pages27
JournalCurrent Medicinal Chemistry
Issue number31
Publication statusPublished - Jan 1 2014


  • Advanced glycation end-products (AGEs)
  • Amyotrophic lateral sclerosis (ALS)
  • Autophagy
  • Misfolded proteins
  • Mitochondria
  • Prionoids
  • Renshaw cells
  • Stem cell therapy

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology
  • Medicine(all)


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