Apoptosis and motor deficits in SPG76 hereditary spastic paraplegia: Calpain 2 inhibition as therapeutic strategy

Area of Science:

• Neuroscience
• Genetics
• Cell Biology

Background:

• Hereditary spastic paraplegia (HSP) is a group of inherited neurological disorders.
• SPG76 is a complex form of HSP linked to mutations in the CAPN1 gene, which encodes calpain 1.
• Calpain 1 and calpain 2 have opposing roles in cell survival and neurodegeneration.

Purpose of the Study:

• To characterize the cellular and molecular consequences of calpain 1 loss in SPG76.
• To investigate therapeutic strategies targeting calpain 2 and pro-survival pathways in SPG76 patient-derived cells.
• To evaluate the efficacy of potential treatments in an in vivo model of SPG76.

Main Methods:

• Fibroblast cells from SPG76 patients with a CAPN1 mutation were analyzed.
• Cellular pathways including Akt, ERK, GSK3β, and autophagy were assessed.
• Responses to ER stress, apoptosis, and cell death were measured.
• In vitro drug screening using calpain inhibitors (olesoxime, MDL28170), naringenin, and tideglusib was performed.
• An in vivo Drosophila model (CalpB KO) was used to assess therapeutic rescue.

Main Results:

• SPG76 patient cells lacking calpain 1 exhibited increased calpain 2 activity, autophagy, ER stress susceptibility, apoptosis, and cell death.
• Inhibition of pro-survival Akt and ERK pathways and reduced GSK3β inhibition were observed.
• Olesoxime, MDL28170, naringenin, and tideglusib showed efficacy in rescuing SPG76 cell pathways.
• Olesoxime and MDL28170 demonstrated effectiveness in reducing calpain activity and apoptosis in vivo.

Conclusions:

• Loss of calpain 1 in SPG76 leads to a complex cellular phenotype involving increased calpain 2 activity and impaired pro-survival signaling.
• Targeting calpain 2 and activating pro-survival pathways represent viable therapeutic strategies for SPG76.
• Olesoxime and MDL28170 show therapeutic potential for SPG76, as evidenced by in vitro and in vivo results.