Combining gene editing and exercise to improve function in ALS

TDP-43 proteinopathy is a key pathological feature of amyotrophic lateral sclerosis (ALS).

• Mutations in the TARDBP gene and cellular stress can lead to the loss of TDP-43 from the nucleus and its accumulation in the cytoplasm.
• Cytoplasmic aggregation of TDP-43 is linked to abnormal splicing of vital neuronal genes like stathmin-2 (STMN2) and unc-13 homolog A (UNC13A).
• This mis-splicing causes the inclusion of cryptic exons in STMN2 and UNC13A mRNA, resulting in non-functional proteins.
• The disruption of STMN2 and UNC13A impacts axonal regeneration and synaptic integrity.
• While splice-switching antisense oligonucleotides and gene-editing can address STMN2 and UNC13A splicing issues, restoring their expression alone does not suffice for neuromuscular junction regeneration or reversing muscle atrophy.

Simplified