C. elegans MANF Homolog Is Necessary for the Protection of Dopaminergic Neurons and ER Unfolded Protein Response

Abstract

Neurotrophic factors (NTFs) are important for the development, function, and survival of neurons in the mammalian system. Mesencephalic astrocyte-derived neurotrophic factor (MANF) and cerebral dopamine neurotrophic factor (CDNF) are two recently identified members of a novel family of NTFs in vertebrates that function to protect dopaminergic neurons. Although these genes are conserved across eukaryotes, their mechanism of neuroprotection is not fully understood. Sequence searches for MANF/CDNF homologs in invertebrates have identified a single ortholog that is most related to MANF. Here we report the in vivo characterization of the MANF gene, manf-1, in the nematode Caenorhabditis elegans. We found that manf-1 mutants have an accelerated, age-dependent decline in the survival of dopaminergic neurons. The animals also show increased endoplasmic reticulum (ER) stress, as revealed by reporter gene expression analysis of hsp-4, an ER chaperone BiP/GRP78 homolog, suggesting that a failure to regulate the ER unfolded protein response (ER-UPR) may be a contributing factor to dopaminergic neurodegeneration. Expression studies of manf-1 revealed that the gene is broadly expressed in a pattern that matches closely with hsp-4. Consistent with the requirements of manf-1 in the ER-UPR, we found that aggregates of α-Synuclein, a major constituent of Lewy bodies, were significantly increased in body wall muscles of manf-1 mutant animals. Overall, our work demonstrates the important role of manf-1 in dopaminergic neuronal survival and the maintenance of ER homeostasis in C. elegans.

Axin Family of Scaffolding Proteins in Development: Lessons from C. elegans

“…One of the ways whereby pry-1-mediated WNT signaling may protect neurons in C. elegans is by regulating the expression of genes that confer neuroprotection. This hypothesis is based on our preliminary observation that the transcription of manf-1, a homolog of mammalian MANF (Mesencephalic astrocyte-derived neurotrophic factor) [131], was significantly downregulated in pry-1 mutant worms (S. Taylor, unpublished) ( Figure 5D). In the future, it will be interesting to investigate pry-1 s role in manf-1 regulation and its link to neuroprotection.…”

MANF Ablation Causes Prolonged Activation of the UPR without Neurodegeneration in the Mouse Midbrain Dopamine System

“…In zebrafish, knock-down of Manf results in a decreased number of dopamine neurons without phenotypic defects (Chen et al, 2012). In nematodes, a mutation in the Manf homologue was suggested to result in the gradual degeneration of dopamine neurons (Richman et al, 2018), but a recent study implicated that MANF-depleted nematodes do not after all display any dopamine phenotype (Hartman et al, 2019). We have shown that conventional MANF knock-out (KO) mice and pancreas-specific conditional KO mice develop insulin-dependent diabetes due to prolonged ER stress in pancreatic b cells, leading to loss of the b cell mass and premature death (Lindahl et al, 2014;Danilova et al, 2019a).…”

Decreased Expression of Cerebral Dopamine Neurotrophic Factor in Platelets of Stroke Patients

“…The neuroprotective effects of CDNF in dopaminergic neuronal populations has also been established in several preclinical models of Parkinson's disease (PD). 20,21 CDNF facilitates neuroprotective effects through regulating protein folding, thereby reducing ER stress caused by aggregated or misfolded proteins. 21 Ischemia is known to induce the ER stress response and initiate the activity of ER stress proteins like CDNF.…”