Parkin deficiency rewires the genetic dependencies that govern neuronal survival

Parkin loss in isogenic Rattus norvegicus Prkn-/- cortical neurons increases death rate 2.6-fold versus wild type, and Parkin re-expression attenuates this effect.

• Why it matters: The prevailing Parkinson’s model centers on mitochondrial quality control, but it does not explain how Parkin deficiency changes which genes neurons depend on for survival.
• What they did: Genome-scale CRISPR screening of 14,646 genes in primary post-mitotic neurons found 160 survival modifiers, and arrayed knockouts with single-cell survival tracking tested gene dependencies under different Parkin statuses.
• The result: Dependencies invert with Parkin status: Rab7a, Cs, or Crym loss kills wild-type but protects Prkn-/- neurons, while Ldha loss kills only Prkn-/- neurons, implying interventions may help or harm depending on genotype.