Cerebral dopamine neurotrophic factor (CDNF) is an unconventional neurotropic factor that modulates unfolded protein response (UPR) pathway signaling and alleviates endoplasmic reticulum (ER) stress providing cytoprotective effects in different models of neurodegenerative disorders. Here, we developed a brain-penetrating peptidomimetic compound based on human CDNF. This compound called HER-096 shows similar potency and mechanism of action as CDNF, and promotes dopamine neuron survival, reduces α-synuclein aggregation and modulates UPR signaling in in vitro models. HER-096 is metabolically stable and able to penetrate to cerebrospinal (CSF) and brain interstitial fluids (ISF) after subcutaneous administration, with an extended CSF and brain ISF half-life compared to plasma. Subcutaneously administered HER-096 modulated UPR pathway activity, protected dopamine neurons, and reduced α-synuclein aggregates and neuroinflammation in substantia nigra of aged mice with synucleinopathy. Peptidomimetic HER-096 is a candidate for development of a disease-modifying therapy for Parkinson’s disease with a patient-friendly route of administration. Display omitted •HER-096 mimics CDNF action by modulating UPR pathway signaling•HER-096 is proteolysis-resistant and can penetrate the blood-brain barrier•HER-096 shows disease modifying potential in an animal model of PD HER-096 is a compound developed based on the active site of the human CDNF protein that potentially can slow down the progression of neurodegeneration. HER-096 is able to penetrate the brain after subcutaneous administration and to protect neurons in animal model of Parkinson’s disease.