Novel views of degradation in amyotrophic lateral sclerosis (ALS)

Proteotoxic stress and protein aggregates have been implicated in Alzheimer`s disease (AD), Parkinson`s disease (PD) and amyotrophic lateral sclerosis (ALS). Although proteasome impairment was previously suggested as a crucial component in ALS pathology, the role of aberrant proteasomal degradation in ALS pathogenesis remains unclear.

By utilizing NucMAPP (see poster # ) we profiled, for the first time, the degradation landscape in ALS. First, we examined global changes in cellular degradation in response to aggregation of the DNA binding protein TDP43, a hallmark of ALS disease. Then, by mapping the degradation landscape of patient-derived ALS motor neurons and their isogenic controls, we could verify novel cytosolic and nuclear degradation substrates that are associated with ALS pathology.

Our analysis revealed a dynamic interplay in the cyto-nuclear degradome and provides insight into aberrant proteasomal degradation in ALS, which may offer novel opportunities for therapeutic intervention.

Finally, as NucMAPP is adaptable to numerous cellular systems, our study affords a novel paradigm by which nuclear-associated diseases may be explored.