Necroptosis in Parkinson's models

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Angelo Iannielli, Vania Broccoli and colleagues (San Raffaele Scientific Institute, Milan, 2018; funded by the European Research Council and Regione Lombardia); Francisca Court's group, Santiago (Oñate et al., 2020); Qisheng Lin and colleagues (2020).

What happened

Necroptosis is a cell-death route distinct from apoptosis. RIPK1 and RIPK3 are kinases (enzymes); MLKL is the protein that ruptures the cell membrane.

• 2018: neurons made from patient stem cells carrying OPA1 mutations died faster, and the necroptosis inhibitor necrostatin-1s (Nec-1s) rescued them. Nec-1s also protected dopamine neurons in MPTP-treated mice (landmark 47 covers patient-cell models; landmark 2 the toxin).
• 2020 (Oñate): necroptosis was active in post-mortem Parkinson's brain tissue and a toxin (6-hydroxydopamine) mouse model. Inhibiting the pathway delayed damage to nerve fibres (axons) in culture, and removing MLKL or RIPK3, or blocking RIPK1 with a drug, reduced dopamine neuron loss and improved movement. The paper has an author correction (Cell Death Differ 2020;27:2294, DOI 10.1038/s41418-020-0507-2); it fixed the details of references 65 and 66 and restored four omitted references, with no change to results (read at nature.com, checked 23 Oct 2026).
• 2020 (Lin): RIP1, RIP3 and MLKL rose in MPTP mice as neurons were lost; necrostatin-1 or RIP3/MLKL knockout reduced the loss.

Why it moved us toward a cure

Earlier cell-death-blocking drugs failed in trials (this branch's verdict). Necroptosis is a different pathway, and drugs that block it already exist: the brain-penetrant RIPK1 inhibitor SAR443820 has been tested in ALS and multiple sclerosis (registry records NCT05237284, NCT05630547).

Outcome

Open. All evidence is preclinical, mostly toxin models, which do not copy Parkinson's slow course. A ClinicalTrials.gov search on 20 Oct 2026 (Parkinson's with RIPK1, RIP1 or necroptosis) found no trials. SAR443820's Phase 2 ALS trial (NCT05237284) was terminated because Part A did not meet its primary endpoint (registry, results posted March 2025), and its MS neurofilament study (NCT05630547) is also terminated. This weakens the case for RIPK1 as a neuroprotective target, though ALS is a different disease.

Sources

• Iannielli et al., Cell Rep 2018;22:2066–2079, DOI 10.1016/j.celrep.2018.01.089 (PMC5842028)
• Oñate et al., Cell Death Differ 2020;27:1169–1185, DOI 10.1038/s41418-019-0408-4 (PMC7205895)
• Lin et al., Lab Invest 2020;100:503–511, DOI 10.1038/s41374-019-0319-5
• Mifflin et al., Nat Rev Drug Discov 2020;19:553–571, DOI 10.1038/s41573-020-0071-y (review)
• ClinicalTrials.gov NCT05237284
• Not yet verified: full texts of Oñate and Lin; any independent replication in a chronic (non-toxin) model; the sponsor and alternative name (DNL788) of SAR443820.