MANF and CDNF as Regulators of Cellular Stress Pathways in Preclinical Models of Neurodegeneration: A Systematic Scoping Review

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Abstract Mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) have emerged as conserved regulators of neuronal stress adaptation across neurodegenerative conditions. Although traditionally classified as neurotrophic factors, accumulating evidence suggests that MANF/CDNF function more broadly as modulators of proteostasis, endoplasmic reticulum (ER) stress signaling, autophagy, and cellular resilience. This systematic scoping review synthesized preclinical evidence on MANF and CDNF in models of neurodegeneration. Following PRISMA-ScR guidelines, searches for Embase, MEDLINE, and Web of Science (2005–2025) identified 3,037 papers, of which 80 met the inclusion criteria. Most studies used rodent models of Parkinson’s disease (PD), Alzheimer’s disease (AD), Amyotrophic Lateral Sclerosis (ALS), Huntington’s disease (HD), stroke, or toxin-induced degeneration, complemented by invertebrate and cell culture systems. Across experimental systems, MANF and CDNF promoted dopaminergic neuron survival, reduced ER stress, improved proteostasis, and enhanced motor outcomes, although the magnitude of these effects differed across disease models and intervention strategies. Mechanistic studies demonstrated modulation of UPR-associated markers, enhanced autophagy clearance, stabilization of lysosomal function, and improved cellular resilience to proteotoxic stress. Collectively, the literature supports a cellular stress-adaptation framework in which MANF and CDNF regulate ER homeostasis, proteostatic balance, autophagy-lysosomal function, and dopaminergic neuron resilience during neurodegeneration.

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