CDNF rescues motor neurons in three animal models of ALS by targeting ER stress

Abstract

One sentence summaryCerebral dopamine neurotrophic factor (CDNF) was found to substantially attenuate amyotrophic lateral sclerosis (ALS)-associated pathology in three preclinical rodent models via modulation of the endoplasmic reticulum (ER) stress, highlighting its potential therapeutic use in this motor neuron disease. AbstractAmyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease primarily afflicting motor neurons (MNs) of the spinal cord, brainstem, and motor cortex, leading to paralysis and eventually death within 3 to 5 years of diagnosis. No cure or effective therapy to halt ALS progression is available. The role of chronic endoplasmic reticulum (ER) stress in the pathophysiology of ALS, as well as a potential drug target, has received increasing attention. Here, we investigated the therapeutic effect of the ER resident protein cerebral dopamine neurotrophic factor (CDNF) in preclinical models of ALS harboring different genetic mutations. We identify that intracerebroventricular (i.c.v.) administration of CDNF significantly halts the progression of the disease and improves motor behavior in TDP43-M337V and SOD1-G93A rodent models of ALS.CDNF rescues MNs in vitro and in vivo from ER stress associated cell death and its beneficial effect is independent of genetic disease etiology. Notably, CDNF regulates the unfolded protein response (UPR) initiated by transducers IRE1α, PERK, and ATF6, thereby enhancing MN survival. Thus, CDNF holds great promise for the design of new rational treatments for ALS.

Beneficial behavioral effects of chronic cerebral dopamine neurotrophic factor (CDNF) infusion in the N171-82Q transgenic model of Huntington’s disease

“…We found that CDNF is neuroprotective against QA toxicity in vitro and in vivo , and CDNF may also promote neurogenesis in vivo 23 . Previously, CDNF has been shown neuroprotective effects in different neuropathological conditions, such as in PD 27 , 37 , 38 , 44 , Alzheimer’s disease (AD) and amyotrophic lateral sclerosis (ALS) 24 .…”

“…Neurotrophic factors (NTFs) are secretory proteins that are involved in the survival, development, differentiation and functional recovery of neurons. There are decreased levels of NTFs in the brains of patients with neurodegenerative diseases including Parkinson´s disease (PD), Alzheimer´s disease (AD) and HD 17 – 19 , and these factors have therefore also been tested in preclinical and clinical trials of Amyotrophic lateral sclerosis (ALS), AD, PD and HD 20 – 24 .…”

“…Previous data on the effects of CDNF on ER stress markers support the hypothesis of direct regulation of UPR pathways by CDNF 22 , 33 . Moreover, recent data showed that CDNF interacts with the main ER chaperone Bip (as known as GRP78) 34 , is upregulated and secreted in response to experimental ER stress, and protects cells from ER stress-induced cell death both in vitro and in vivo 24 , 35 .…”

Cerebral dopamine neurotrophic factor reduces α-synuclein aggregation and propagation and alleviates behavioral alterations in vivo

“…Extracellular CDNF might act to some extent by binding to α-synuclein or by decreasing the intake of α-synuclein via plasma membrane receptors responsible for α-synuclein uptake, such as heparan sulfate 45 or LAG3. 46 Also, CDNF infusion into the striatum has been shown to modulate UPR signaling in stressed cells, 47 and CDNF added to culture media of stressed neurons has been shown to modulate ER stress, 48 which suggests an indirect effect of CDNF on α-synuclein aggregation intermediated by ER stress modulation. Therefore, the reason we observe inhibition of α-synuclein oligomerization and a modest effect on fibril uptake by CDNF, but increased number of pSer129 inclusions in the soma of neurons and no discernible effect on these inclusions at the time point measured in rodent brains, likely has to do with the localization of endogenous CDNF or timing of exogenous CDNF administration.…”

CDNF and MANF regulate ER stress in a tissue-specific manner

“…CDNF and MANF are able to downregulate UPR signaling after ER stress induction in different cell types [ 2 , 17 ]. All three UPR pathways are downregulated upon CDNF treatment in SOD1 mice modeling amyotrophic lateral sclerosis (ALS) [ 18 ]. The loss of endogenous MANF in mice causes increased expression of UPR genes in the pancreas, brain, pituitary gland, and liver [ 12 , 13 , 19 , 20 ].…”