Breitet sich die sporadisch auftretende amyotrophe Lateralsklerose über axonale Verbindungen aus?

Zusammenfassung

Der pathologische Prozess einer sporadisch auftretenden amyotrophen Lateralsklerose (sALS) ist mit dem Auftreten zytoplasmatischer Einschlusskörper eines normalerweise im Zellkern vorkommenden Proteins (TDP-43) verbunden und ergreift nur wenige Arten langaxoniger Projektionsneurone. Die Riesenpyramidenzellen von Betz im primären motorischen Neokortex und die α-Motorneurone im unteren Hirnstamm und Rückenmark sind früh ergriffene Zellformen. Im zentralen Nervensystem des Menschen sind diese beiden Zellarten durch axonale Projektionen monosynaptisch verbunden. Im Verlauf einer sALS verlieren die Zellkerne affizierter Neurone graduell ihre Immunoreaktivität für TDP-43. Bei α-Motorneuronen entstehen unlösliche TDP-43-Einschlüsse im Zellleib, während in Betz-Zellen derartige Aggregatbildungen zunächst ausbleiben. Es erscheint daher möglich, dass in Betz-Zellen anfänglich eine im Zytoplasma noch lösliche Form des TDP-43 entsteht, die in das Axoplasma gerät, über direkte synaptische Kontakte übertragen wird und im nachfolgenden Neuron erneut die Dysregulation und Aggregation des TDP-43 auslöst. Das im Verlauf einer sALS entstehende Ausbreitungsmuster der Schädigungen ist mit der Vorstellung vereinbar, dass ein zellenschädigendes Agens über axonale Kontakte von kortikalen Projektionsneuronen auf nachfolgende Neuronen übertragen wird und dort den pathologischen Prozess erneut induziert.

Abstract

The 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 two 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, induce 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.

Schlüsselwörter

α-Motorneuron - monosynaptische Transmission - amyotrophe Lateralsklerose - Betz-Zellen - TDP-43

Key words

α-motor neuron - monosynaptic transmission - amyotrophic lateral sclerosis - Betz cells - TDP-43

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