Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

Abstract

IntroductionAmyotrophic lateral sclerosis (ALS) is characterized by rapid progressive paralysis of the striated skeletal musculature [1,2]. The present review focuses on sporadic disease (sALS), which constitutes the majority of cases without a known genetic mutation. Clinically similar but inherited (familial) forms that display very diverse pathologies [3][4][5][6][7] are not taken into account here.The pathological process underlying sALS entails abnormal changes of an endogenous and predominantly intranuclear protein, TDP-43 (transactive response DNA-binding protein 43). Following nuclear clearance, the protein remains delocalized in the cytoplasm of susceptible nerve cells, where it undergoes defective phosphorylation and conformational change followed by ubiquitination, which ultimately prevent its re-entry into the nuclear compartment [7][8][9][10][11].The pathomechanisms that lead to the dysfunction and death of involved cells are still unknown. Along with a "loss of function" attributable to the loss of intranuclear TDP-43 expression accompanied by disrupted RNA metabolism, a "gain of function" mechanism owing to a noxious effect on cells by toxic TDP-43 forms has been discussed [7,12] Which Nerve Cell Types Develop TDP-43-immunoreactive Inclusions in sALS?The abnormal nuclear clearance and development of cytoplasmic TDP-43-immunopositive inclusions are confined to a few types ABsTr AC TThe pathological process underlying sporadic amyotrophic lateral sclerosis (sALS) that is associated with the formation of cytoplasmic inclusions of a nuclear protein (TDP-43) is confined to only a few types of long-axoned projection neurons. The giant Betz pyramidal cells of the primary motor neocortex as well as large α-motor neurons of the lower brainstem and spinal cord become involved early. In the human brain, these 2 neuronal types are to a large extent interconnected by monosynaptic axonal projections. The cell nuclei of affected neurons gradually forfeit their normal expression of the protein TDP-43. In α-motor neurons, this nuclear loss is followed by the formation of insoluble TDP-43-immunopositive inclusions in the cytoplasm, whereas in Betz cells the loss of nuclear expression remains for an unknown period of time unaccompanied by somatodendritic and/or axoplasmic aggregations. It is possible that in cortical pyramidal cells (Betz cells) the nuclear clearing initially leads to the formation of an abnormal but still soluble cytoplasmic TDP-43 which may enter the axoplasm and, following transmission via direct synaptic contacts, induces anew TDP-43 dysregulation and aggregation in recipient neurons. The trajectory of the spreading pattern that consecutively develops during the course of sALS is consistent with the dissemination from chiefly cortical projection neurons via axonal transport through direct synaptic contacts leading to the secondary induction of TDP-43-containing inclusions within recipient nerve cells in involved subcortical regions. E136Braak H et al. Does Sporadic Amyotrophic Lateral … Neurolo...

MRI-Based Mapping of Cerebral Propagation in Amyotrophic Lateral Sclerosis

“…A multicentre study of eight contributing centers with 253 ALS patients and 189 healthy controls ( Müller et al, 2016 ) confirmed the most significant alterations to be localized in the CST (corresponding to stage 1) and found additional significant WM tract changes in the frontal lobe, the brainstem, and hippocampal regions (corresponding to stages 2–4). The localization of these DTI-based in vivo results were in accordance with the definition of the post-mortem neuropathological stages ( Brettschneider et al, 2013 ; Braak et al, 2017 ).…”

FUS pathology in ALS is linked to alterations in multiple ALS-associated proteins and rescued by drugs stimulating autophagy

“…A defining trait of ALS is the progression of motor dysfunction. Although disease onset is typically focal, symptoms rapidly spread in a manner that reflects the organization of the underlying neuronal circuitry, usually in a corticofugal fashion [ 3 , 4 ]. Although ALS-causing mutations affect genes, such as FUS, that are ubiquitously and constitutively expressed, MNs appear to be particularly vulnerable.…”

Identical patterns of cortico-efferent tract involvement in primary lateral sclerosis and amyotrophic lateral sclerosis: A tract of interest-based MRI study

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