Amyotrophic lateral sclerosis and lead: A systematic update

Heavy metals are considered to be among the leading environmental factors that trigger amyotrophic lateral
sclerosis (ALS). However, no convincing biopathological mechanism and therapeutic clinical implication of such
metals in ALS pathogenesis have been established. This is partly attributable to the technical and scientific
difficulties in demonstrating a direct and causative role of heavy metals in the onset of ALS in patients. However,
a body of epidemiological, clinical and experimental evidences suggest that lead (Pb), more than other metals,
could actually play a major role in the onset and progression of ALS. Here, to clarify the nature of the association
and the causative role of Pb in ALS, we comprehensively reviewed the scientific literature of the last decade with
objective database searches and the methods typically adopted in systematic reviews, critically analysing and
summarising the various scientifically sound evidence on the relationship between ALS and Pb. From these tasks,
we noted a number of multidisciplinary associations between ALS and Pb, and specifically the importance of
occupational exposure to Pb in ALS development and/or progression. We also report the possible involvement of
TAR DNA binding protein (TDP-43)-based molecular mechanism in Pb-mediated ALS, although these data rely
on a single study, which included both in vitro experiments and an animal model, and are therefore still preliminary. Finally, we briefly examined whether this knowledge could inspire new targeted therapies and policies
in the fight against ALS. .