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

Abstract

A molecular hallmark in Parkinson's disease (PD) pathogenesis are a-synuclein aggregates. Cerebral dopamine neurotrophic factor (CDNF) is an atypical growth factor that is mostly resident in the endoplasmic reticulum but exerts its effects both intracellularly and extracellularly. One of the beneficial effects of CDNF can be protecting neurons from the toxic effects of a-synuclein. Here, we investigated the effects of CDNF on a-synuclein aggregation in vitro and in vivo. We found that CDNF directly interacts with a-synuclein with a K D = 23 ± 6 nM and reduces its auto-association. Using nuclear magnetic resonance (NMR) spectroscopy, we identified interaction sites on the CDNF protein. Remarkably, CDNF reduces the neuronal internalization of a-synuclein fibrils and induces the formation of insoluble phosphorylated a-synuclein inclusions. Intra-striatal CDNF administration alleviates motor deficits in rodents challenged with a-synuclein fibrils, though it did not reduce the number of phosphorylated a-synuclein inclusions in the substantia nigra. CDNF's beneficial effects on rodent behavior appear not to be related to the number of inclusions formed in the current context, and further study of its effects on the aggregation mechanism in vivo are needed. Nonetheless, the interaction of CDNF with a-synuclein, modifying its aggregation, spreading, and associated behavioral alterations, provides novel insights into the potential of CDNF as a therapeutic strategy in PD and other synucleinopathies.

Cerebral dopamine neurotrophic factor protects and repairs dopamine neurons by novel mechanism

“…In addition to neuroprotective and neuroregenerative activities that, similarly to other NTFs, partially occur via the activation of PI3 kinase-Akt pathways [ 89 , 114 ], CDNF also counteracts cell death by regulating UPR pathways in the ER [ 70 , 89 ]. CDNF protects against toxicity of αSyn oligomers in vitro [ 30 ], and was recently shown to directly interact with αSyn, reduce propagation of αSyn aggregation and alleviate behavioral deficits induced by αSyn fibrils in mice [ 115 ]. CDNF also reduces the synthesis and release of pro-inflammatory cytokines decreasing neuroinflammation [ 108 , 109 , 114 , 116 ].…”

Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model

“…In contrast, the α-synuclein rat model of PD is ideal to characterize DA neuron dysfunction, accompanied by extensive α-syn accumulation and a prominent inflammatory response, which may provide closer investigation of survival, long-term functionality, and integrity of the cells in rVM graft [ 93 ]. However, as our previous study showed [ 94 ], injection of preformed α-synuclein fibrils to rodent resulted in behavior alternations but did not cause significant decrease in TH-positive fiber density within striatum. Therefore, we have to establish a synucleinopathy PD rodent model that better mimics the disease pathology, including α-synuclein accumulation, inflammation, and progressive DA neuron cell loss, to assess how a pathological host environment affects the transplanted cells, and allow for future studies of CDNF’s regenerative effect.…”

CDNF Interacts with ER Chaperones and Requires UPR Sensors to Promote Neuronal Survival

“…While extracellularly applied CDNF has been shown to be both neuroprotective and neurorestorative in animal models of neuronal damage [ 1 , 30 , 37 , 43 , 44 ], the intracellular effects of CDNF remain relatively poorly studied. Therefore, we used CDNF overexpression by neuronal plasmid microinjection to investigate its effects on neuronal survival in an ER stress-related apoptosis model in vitro.…”

“…CDNF was recently shown to interact directly with alpha-synuclein (αSyn), a major protein of Lewy bodies characteristic for the neuropathology of PD, decreasing αSyn cell entry and reducing αSyn phosphorylation, as well improving locomotor activity in a rodent αSyn model of PD [ 37 ]. However, the exact mechanism and biological consequences of this interaction remain unclear.…”