CDNF protein seen to improve motor coordination in Huntington’s mice
Study findings support CDNF as potential therapy for rare disease
The success of CDNF — fully, cerebral dopamine neurotrophic factor — in improving motor coordination in a mouse model of Huntington’s disease supports this protein’s development as a potential therapy for the rare disorder, according to a new study.
In the study, CDNF was injected into the brain of a mouse model of Huntington’s, a neurodegenerative disease that results in uncontrolled movements and cognitive problems, where it showed benefit. These findings build upon the treatment’s previously reported success in a rat model with induced Huntington’s.
“Collectively our results indicate that CDNF might be a potential drug candidate for the treatment of HD [Huntington’s disease],” the researchers wrote, noting there “is no effective treatment to stop neurodegeneration in the affected brain areas of HD patients.”
The study, “Beneficial behavioral effects of chronic cerebral dopamine neurotrophic factor (CDNF) infusion in the N171-82Q transgenic model of Huntington’s disease,” was published in the journal Nature Scientific Reports.
Seeking a potential therapy for Huntington’s
An excess of repeats, called CAG triplets, within the HTT gene is the underlying cause of Huntington’s. These CAG triplets lead to the production of an abnormally long huntingtin protein that forms toxic clumps and causes nerve damage.
Neurotrophic factors, whose levels are reduced in the brains of people with neurodegenerative diseases such as Huntington’s, are naturally secreted proteins “involved in survival, development, [maturation] and functional recovery of neurons [nerve cells],” the researchers wrote.
CDNF, a protein with neurotrophic properties, is found in the blood and fluid surrounding the brain and spinal cord, as well as in brain regions affected by Huntington’s — specifically, the cortex and striatum.
Treatment with the protein was shown to protect and restore neurons in rodent and non-primate models of Parkinson’s disease, another neurodegenerative condition. CDNF also reduced some Parkinson’s signs and symptoms in Parkinson’s patients in early trials.
Because of the similarities between many neurodegenerative conditions, researchers at the University of Helsinki, in Finland, previously had evaluated the effects of injecting CDNF directly into the striatum of rats with induced Huntington’s. Data showed that a single injection protected nerve cells from degeneration and improved the animials’ motor performance.
To further investigate its potential as a Huntington’s therapy, the team now tested CDNF in a mouse model of this disease. Called N171-82Q, this Huntington’s mouse model carries excess CAG triplets in the HTT gene.
CDNF was continuously infused directly into the striatum of N171-82Q mice for four weeks, or about one month. The team then used validated tests to assess motor coordination in treated versus untreated animals.
The results showed that CDNF prevented motor function worsening and significantly improved balance performance in female mice. However, no significant effects were observed in male mice.
The clasping of the hind limbs, which usually increases during disease progression, was less frequent in CDNF-treated mice than in untreated animals, but this difference reached statistical significance only among males.
Still, “N171-82Q females showed a decrease in the number of animals with clasped hindlimbs even after the minipump’s removal, which indicates the prolongation of the positive effect of CDNF in the brain tissue,” the team wrote.
“Taken together, the results with the behavioral tests reveal that CDNF has a positive effect on motor coordination in the N171-82Q mice,” the researchers wrote.
Therapy candidate shows potential to ease motor impairments
In addition, there was an age-dependent increase in the number of toxic huntingtin clumps in the animal model’s striatum and cortex, reflecting “a correlation between the deterioration of motor behavior observed in these mice and the appearance of the mHtt [mutant huntingtin] aggregates,” they wrote.
While CDNF treatment tended to reduce the number of huntingtin clumps in the striatum of female mice, the findings were not significantly different from untreated mice in either sex.
“The failure to reach statistical significance in these studies could be due to the low number of mice analyzed or the inaccuracy in detecting the real toxic species of mHtt that may be affected by CDNF,” the researchers wrote.
Further experiments in N171-82Q mice demonstrated a significantly lower activity of BDNF, the gene that encodes a classic neurotrophic factor called BDNF, in the hippocampus, a brain region also affected in Huntington’s.
The results support that CDNF significantly improves behavior in the N171-82Q mouse model of [Huntington’s disease] that may be beneficial for future therapies and as such warrants further investigations.
CDNF treatment was found to significantly increase hippocampus BDNF gene activity in the mice, and to significantly raise BDNF protein levels in lab-grown mouse striatal neurons producing mutant huntingtin.
These findings highlight that CDNF lessened motor dysfunction in N171-82Q mice and improved motor coordination in N171-82Q females, while showing a tendency to reduce huntingtin clumps in the striatum of female mice and to increase brain BDNF levels.
“The results support that CDNF significantly improves behavior in the N171-82Q mouse model of [Huntington’s disease] that may be beneficial for future therapies and as such warrants further investigations,” the researchers concluded.