Fig. 9: Schematic representation of potential processes triggered by loss of ASRGL1 resulting in TDP-43 proteinopathy in ALS.

(1) TDP-43 is involved in RNA transcription, splicing, stability, transport, and translation. (2) It is predominantly found in the cell nucleus but to perform its functions, TDP-43 is shuttled in its native form from the nucleus to the cytoplasm. (3) Isoaspartates (I) are formed spontaneously and non-enzymatically by deamidation of asparagine residues (N) of TDP-43. They introduce a kink in the peptide chain, favoring misfolding. Misfolded and fragmented TDP-43 are ubiquitinated for proteasome degradation. (4) Since proteases do not recognize isoaspartates residues, they must be cleaved from the peptide chain by ASRGL1 in the perinuclear region for the misfolded/fragmented protein to be (5) degraded by the proteasome. (6) The HML-2 copy is in the opposite strand of the ASRGL1 gene thus, the RNA of HML-2 is complementary to the RNA of ASRGL1 (HML-2 cDNA could also base pair with the ASRGL1 RNA). (7) HML-2 sequences could cause an antisense silencing on ASRGL1, interfering with its splicing, translation and/or activating the RNA-induced silencing complex. (8) If ASRGL1 is inactivated or depleted, isoaspartates residues cannot get cleaved and the aberrant TDP-43 forms (hyper-phosphorylated, misfolded and fragmented peptides) do not get degraded, (9) leading to a toxic aggregation in the cytoplasm. (Black arrows indicate physiological processes and red arrows indicate pathological processes).