Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTA4SHR)

• DTT Name: C9orf72 messenger RNA (C9orf72 mRNA)
• Gene Name: C9orf72
• DTT Type: Clinical trial target; [1]
• UniProt ID: CI072_HUMAN
• TTD ID: T70134
• Sequence:
  MSTLCPPPSPAVAKTEIALSGKSPLLAATFAYWDNILGPRVRHIWAPKTEQVLLSDGEIT
  FLANHTLNGEILRNAESGAIDVKFFVLSEKGVIIVSLIFDGNWNGDRSTYGLSIILPQTE
  LSFYLPLHRVCVDRLTHIIRKGRIWMHKERQENVQKIILEGTERMEDQGQSIIPMLTGEV
  IPVMELLSSMKSHSVPEEIDIADTVLNDDDIGDSCHEGFLLNAISSHLQTCGCSVVVGSS
  AEKVNKIVRTLCLFLTPAERKCSRLCEAESSFKYESGLFVQGLLKDSTGSFVLPFRQVMY
  APYPTTHIDVDVNTVKQMPPCHEHIYNQRRYMRSELTAFWRATSEEDMAQDTIIYTDESF
  TPDLNIFQDVLHRDTLVKAFLDQVFQLKPGLSLRSTFLAQFLLVLHRKALTLIKYIEDDT
  QKGKKPFKSLRNLKIDLDLTAEGDLNIIMALAEKIKPGLHSFIFGRPFYTSVQERDVLMT
  F
• Function: Component of the C9orf72-SMCR8 complex, a complex that has guanine nucleotide exchange factor (GEF) activity and regulates autophagy. In the complex, C9orf72 and SMCR8 probably constitute the catalytic subunits that promote the exchange of GDP to GTP, converting inactive GDP-bound RAB8A and RAB39B into their active GTP-bound form, thereby promoting autophagosome maturation. The C9orf72-SMCR8 complex also acts as a regulator of autophagy initiation by interacting with the ATG1/ULK1 kinase complex and modulating its protein kinase activity. Positively regulates initiation of autophagy by regulating the RAB1A-dependent trafficking of the ATG1/ULK1 kinase complex to the phagophore which leads to autophagosome formation. Acts as a regulator of mTORC1 signaling by promoting phosphorylation of mTORC1 substrates. Plays a role in endosomal trafficking. May be involved in regulating the maturation of phagosomes to lysosomes (By similarity). Regulates actin dynamics in motor neurons by inhibiting the GTP-binding activity of ARF6, leading to ARF6 inactivation. This reduces the activity of the LIMK1 and LIMK2 kinases which are responsible for phosphorylation and inactivation of cofilin, leading to cofilin activation. Positively regulates axon extension and axon growth cone size in spinal motor neurons. Plays a role within the hematopoietic system in restricting inflammation and the development of autoimmunity (By similarity).
• KEGG Pathway:
  Autophagy - animal (hsa04140)
  Amyotrophic lateral sclerosis (hsa05014)
  Pathways of neurodegeneration - multiple diseases (hsa05022)

Molecular Interaction Atlas (MIA) of This DTT

1 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
IONIS-C9Rx	DM6PDX2	Amyotrophic lateral sclerosis	8B60.0	Phase 2	[1]

References

• [1] Clinical pipeline report, company report or official report of Ionis Pharmaceuticals.