Trancriptional profile of iGNs and iMNs after TDP-43 knockdown

Research Hypothesis
The study hypothesized that while TDP-43 loss-of-function is a near-universal hallmark of ALS, its molecular consequences—specifically regarding gene expression and cryptic splicing—are cell-type specific (glutamatergic induced neurons - iGNs versus cholinergic induced neurons - iMNs) . We further hypothesized that the presence of astrocytes (iAs) would modulate the detectable splicing repertoire of human induced neurons (iNs), providing a more clinically relevant representation of the disease environment.

What the Data Shows
Subtype-Specific Signatures: The data reveals distinct transcriptomic profiles for iGNs and iMNs. While TDP-43 depletion affected 92 genes in iMNs and 52 in iGNs, only 33 genes overlapped between the two subtypes.
Conserved Pathological Core: Despite low overall overlap, a conserved set of ALS-relevant targets—including STMN2, UNC13A, CAMK2B, and ATG4B—were consistently downregulated and mis-spliced across both populations.
Glial Influence: The inclusion of astrocytes (iNs+iAs) facilitated the detection of additional cryptic events, most notably in HDGFL2, which matched patient-derived cerebrospinal fluid data .

Data organization:
Gene counts - "Counts_processed_pure_iGNs_iMNs.csv" (pure iNs) and "Counts_processed_iGNs_iAs.csv" (co-culture iNs+iAs)
Splicing variants frequency - "Splicing_iMN_iGN_sgvc_combined.rds" (pure iNs) and "Splicing_ioGN_ioAs_sgvc_combined.rds" (co-culture iNs+iAs)