Can regional spreading of amyotrophic lateral sclerosis motor symptoms be explained by prion-like propagation?

Abstract

Progressive accumulation of specific misfolded protein is a defining feature of amyotrophic lateral sclerosis (ALS), similarly seen in Alzheimer disease, Parkinson disease, Huntington disease and Creutzfeldt–Jakob disease. The intercellular transfer of inclusions made of tau, α-synuclein and huntingtin has been demonstrated, revealing the existence of mechanisms reminiscent of those by which prions spread through the nervous system. Evidence for such a prion-like propagation mechanism has now spread to the major misfolded proteins, superoxide dismutase 1 (SOD1) and the 43 kDa transactive response DNA binding protein (TDP-43), implicated in ALS. The focus in this review is on what is known about ALS progression in terms of clinical as well as molecular aspects. Furthermore, the concept of ‘propagation’ is dissected into contiguous and non-contiguous types, and this concept is expanded to the severity of the focal symptom as well as its regional spread which can be explained by cell to cell propagation in the local neuron pool.

Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

“…Anterograde axonal transport of the soluble protein could permit it to reach the presynaptic terminals of the Betz cells, where its transsynaptic (cell-to-cell) transmission to the corresponding α-motor neurons of the spinal cord and brainstem could lead anew therein to the pathological dysregulation and prion-like seeded propagation of TDP-43 [42]. According to this hypothesis, the emergence of cytoplasmic aggregates within target neurons would mostly interfere with the ensuing spread of the pathology to the immediately following neuron in the neuronal chain (▶ Fig.…”

Prediction of prognosis of ALS: Importance of active denervation findings of the cervical-upper limb area and trunk area

“…In needle EMG of the trunk area, muscles of the thoracic spinal cord are tested, including the paraspinal muscles and abdominal rectus muscle (23,24). Degeneration of motor neurons may spread contiguously throughout the threedimensional anatomy of connected and neighboring neurons in ALS (25,26), and this may explain upper limb dysfunction resulting from proximal progression of denervation of the trunk area and walking disability due to distal progression.…”

Cross-Sectional Survey of Relevant Literatures as to the Current Proposed Disease Mechanisms and Treatments of Amyotrophic Lateral Sclerosis (ALS)

“…Many of these mutants have phenotypic effects directly influenced by copy number of their aberrant proteins 45 which are best assessed by RT-qPCR. 47 This theory is generally accepted among the ALS community as a likely mechanism to explain SALS with SOD1 abnormalities. SOD has also been implicated as an intermediate in the ER damage cascade, with mutant SOD1 inappropriately utilizing PDI.…”