TY - JOUR
T1 - Deciphering spreading mechanisms in amyotrophic lateral sclerosis
T2 - Clinical evidence and potential molecular processes
AU - Pradat, Pierre François
AU - Kabashi, Edor
AU - Desnuelle, Claude
PY - 2015/1/1
Y1 - 2015/1/1
N2 - Purpose of review The aim of this review is to refer to recent arguments supporting the existence of specific propagation mechanisms associated with spreading of neuron injury in amyotrophic lateral sclerosis (ALS). Recent findings Misfolded ALS-linked protein accumulation can induce aggregation of their native equivalent isoforms through a mechanism analogous to the infectious prion proteins initiation and its propagation. Summary Although ALS is clinically heterogeneous, a shared characteristic is the focal onset and the progressive extension to all body regions. Being viewed until now as just summation of the increased number of affected neurons, dispersion is now rather considered as the result of a seeded self-propagating process. A sequential regional spreading pattern is supported by the distribution of TDP-43 aggregates in ALS autopsy cases. Electrophysiology and advanced neuroimaging methods also recently provided some evidence for propagation of lesions both in the brain and spinal cord, more longitudinal studies being still needed. Lesions are supposed to spread cell-to-cell regionally or through connected neuronal pathway. At the molecular level, the prion-like spreading is an emerging mechanism hypothesis, but other machineries such as those that are in charge of dealing with misfolded proteins and secretion of deleterious peptides may be involved in the propagation of neuron loss. Deciphering the mechanisms underlying spreading of ALS symptoms is of crucial importance to better understand this neurodegenerative disease, build new and appropriate animal models and to define novel therapeutic targets.
AB - Purpose of review The aim of this review is to refer to recent arguments supporting the existence of specific propagation mechanisms associated with spreading of neuron injury in amyotrophic lateral sclerosis (ALS). Recent findings Misfolded ALS-linked protein accumulation can induce aggregation of their native equivalent isoforms through a mechanism analogous to the infectious prion proteins initiation and its propagation. Summary Although ALS is clinically heterogeneous, a shared characteristic is the focal onset and the progressive extension to all body regions. Being viewed until now as just summation of the increased number of affected neurons, dispersion is now rather considered as the result of a seeded self-propagating process. A sequential regional spreading pattern is supported by the distribution of TDP-43 aggregates in ALS autopsy cases. Electrophysiology and advanced neuroimaging methods also recently provided some evidence for propagation of lesions both in the brain and spinal cord, more longitudinal studies being still needed. Lesions are supposed to spread cell-to-cell regionally or through connected neuronal pathway. At the molecular level, the prion-like spreading is an emerging mechanism hypothesis, but other machineries such as those that are in charge of dealing with misfolded proteins and secretion of deleterious peptides may be involved in the propagation of neuron loss. Deciphering the mechanisms underlying spreading of ALS symptoms is of crucial importance to better understand this neurodegenerative disease, build new and appropriate animal models and to define novel therapeutic targets.
KW - Amyotrophic lateral Sclerosis
KW - Fused In Sarcoma
KW - Neuroimaging
KW - Prion-Like Mechanism
KW - Spreading
KW - Superoxide Dismutase 1
KW - Tdp-43
UR - http://www.scopus.com/inward/record.url?scp=84941777004&partnerID=8YFLogxK
U2 - 10.1097/WCO.0000000000000239
DO - 10.1097/WCO.0000000000000239
M3 - Review article
C2 - 26356410
AN - SCOPUS:84941777004
SN - 1350-7540
VL - 28
SP - 455
EP - 461
JO - Current Opinion in Neurology
JF - Current Opinion in Neurology
IS - 5
ER -