Title:Cell to Cell Spreading of Misfolded Proteins as a Therapeutic Target in Motor Neuron Disease
Volume: 21
Issue: 31
Author(s): Livia Pasquali, Paola Lenzi, Francesca Biagioni, Gabriele Siciliano and Francesco Fornai
Affiliation:
Keywords:
Advanced glycation end-products (AGEs); amyotrophic lateral sclerosis (ALS); autophagy; misfolded proteins;
mitochondria; prionoids; Renshaw cells; stem cell therapy.
Abstract: 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 cell to-
cell 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.