Survival in sporadic ALS is associated with lower p62 burden in the spinal cord

Abstract

The autophagy marker p62 appears as a consistent component of pathological aggregates in amyotrophic lateral sclerosis (ALS) and its modulation to facilitate protein degradation has been proposed as a potential therapeutic target. Importantly, recent studies have implicated diffuse phosphorylated TDP-43 inclusions that are immuno-negative for p62 in more rapid disease, highlighting the need for better understanding of p62 involvement in ALS pathogenesis. The present study set out to assess p62 pathology in the motor neurons of 31 patients with sporadic ALS that had either a short (<2 years) or longer (4-7 years) disease duration to determine its association with pTDP-43 pathology, motor neuron loss, and survival in sporadic disease. Our results identified significantly more cytoplasmic p62 aggregates in the spinal cord of patients with a shorter survival. Disease duration demonstrated a negative association with p62 burden and density of remaining motor neurons in the spinal cord, suggesting that survival in sporadic ALS is associated with the successful clearance of lower motor neurons with p62 aggregates. These findings implicate the autophagy pathway in ALS survival and provide support for further study of p62 as a potential prognostic biomarker in ALS.

Keywords: Amyotrophic lateral sclerosis; Motor neurons; p62 pathology; pTDP-43.

Figure 1.

Density (mean ± SE) of motor neurons in the spinal cord (A) and density of motor neurons with cytoplasmic p62-immunoreactive aggregates in the spinal cord (B–E) of ALS cases with a short (<2 years) or longer (4–7 years) disease duration. A significant positive association was identified between the density of p62 aggregates and surviving motor neurons (MNs) in the spinal cord (F). Increasing disease duration was associated with decreasing density of p62 aggregates (G) and surviving motor neurons in the spinal cord (H). SLI, skein-like inclusions. *p < 0.05; **p < 0.005.

Figure 2.

Morphology of cytoplasmic p62-immunoreactive inclusions in the lower motor neurons. (A, C) Skein-like inclusions (B), dense round inclusion, and (D) dot-like inclusions.