Neurotrophic factors are promising candidates for the treatment of Parkinson's disease (PD). Mesencephalic astrocyte-derived neurotrophic factor (MANF) belongs to a novel evolutionarily conserved family of neurotrophic factors. We examined whether MANF has neuroprotective and neurorestorative effect in an experimental model of PD in rats. We also studied the distribution and transportation of intrastriatally injected MANF in the brain and compared it with glial cell line-derived neurotrophic factor (GDNF). Unilateral lesion of nigrostriatal dopaminergic system was induced by intrastriatal injection of 6-hydroxydopamine (6-OHDA). Amphetamine-induced turning behavior was monitored up to 12 weeks after the unilateral lesion. The local diffusion at the injection site and transportation profiles of intrastriatally injected MANF and GDNF were studied by immunohistochemical detection of the unlabeled growth factors as well as by autoradiographic and gamma counting detection of 125 I-labeled trophic factors. Intrastriatally injected MANF protected nigrostriatal dopaminergic nerves from 6-OHDA-induced degeneration as evaluated by counting tyrosine hydroxylase (TH)-positive cell bodies in the substantia nigra (SN) and TH-positive fibers in the striatum. More importantly, MANF also restored the function of the nigrostriatal dopaminergic system when administered either 6 h before or 4 weeks after 6-OHDA administration in the striatum. MANF was distributed throughout the striatum more readily than GDNF. The mechanism of MANF action differs from that of GDNF because intrastriatally injected 125 I-MANF was transported to the frontal cortex, whereas 125 I-GDNF was transported to the SN. Our results suggest that MANF is readily distributed throughout the striatum and has significant therapeutic potential for the treatment of PD.

Highlights d A mass departure of ER-resident proteins occurs in response to ER calcium depletion d KDELR2 and KDELR3, but not KDELR1, are unfolded protein response genes d KDELR2 and KDELR3 upregulation by ER calcium loss counteracts ER protein loss d Stabilizing calcium and increasing KDEL receptor expression have therapeutic potential

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Highlights d Methods are described for cell-specific genome modification in the adult rat brain d Transgenic rats were engineered to express Cre-dependent Cas9 or Cas9 nickase d A Cre driver rat for dopaminergic neurons and an mCherry Cre reporter rat were made d The first transgenic rat made by CRISPR and spermatogonial stem cells is described