Histopathological examinations demonstrated that loss of SQSTM1 accelerated motor neuron degeneration with accompanying the preferential accumulation of ubiquitin-positive aggregates in spinal neurons.
Interestingly, we report for the first time pathological hallmarks of SPG11 in neurons that include intracytoplasmic granular lysosome-like structures mainly in supratentorial areas, and others in subtentorial areas that are partially reminiscent of those observed in amyotrophic lateral sclerosis, such as ubiquitin and p62 aggregates, except that they are never labelled with anti-TDP-43 or anti-cystatin C. The neuropathological overlap with amyotrophic lateral sclerosis, associated with some shared clinical manifestations, opens up new fields of investigation in the physiopathological continuum of motor neuron degeneration.
Our findings provide evidence of a direct genetic role for p62 in ALS pathogenesis and suggest that regulation of protein degradation pathways may represent an important therapeutic target in motor neuron degeneration.