SINEUP Non-coding RNA Targeting GDNF Rescues Motor Deficits and Neurodegeneration in a Mouse Model of Parkinson's Disease

Mol Ther. 2020 Feb 5;28(2):642-652. doi: 10.1016/j.ymthe.2019.08.005. Epub 2019 Aug 16.


Glial cell-derived neurotrophic factor (GDNF) has a potent action in promoting the survival of dopamine (DA) neurons. Several studies indicate that increasing GDNF levels may be beneficial for the treatment of Parkinson's disease (PD) by reducing neurodegeneration of DA neurons. Despite a plethora of preclinical studies showing GDNF efficacy in PD animal models, its application in humans remains questionable for its poor efficacy and side effects due to its uncontrolled, ectopic expression. Here we took advantage of SINEUPs, a new class of antisense long non-coding RNA, that promote translation of partially overlapping sense protein-coding mRNAs with no effects on their mRNA levels. By synthesizing a SINEUP targeting Gdnf mRNA, we were able to increase endogenous GDNF protein levels by about 2-fold. Adeno-associated virus (AAV)9-mediated delivery in the striatum of wild-type (WT) mice led to an increase of endogenous GDNF protein for at least 6 months and the potentiation of the DA system's functions while showing no side effects. Furthermore, SINEUP-GDNF was able to ameliorate motor deficits and neurodegeneration of DA neurons in a PD neurochemical mouse model. Our data indicate that SINEUP-GDNF could represent a new strategy to increase endogenous GDNF protein levels in a more physiological manner for therapeutic treatments of PD.

Keywords: AAV; GDNF; Parkinson’s disease; SINEUP; gene therapy; non-coding RNA.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Corpus Striatum / metabolism
  • Corpus Striatum / pathology
  • Dependovirus / genetics
  • Disease Models, Animal
  • Dopaminergic Neurons / metabolism
  • Gene Expression Regulation
  • Gene Transfer Techniques
  • Genetic Vectors / genetics
  • Glial Cell Line-Derived Neurotrophic Factor / genetics*
  • Glial Cell Line-Derived Neurotrophic Factor / metabolism
  • Humans
  • Immunohistochemistry
  • Mice
  • Motor Neurons / metabolism*
  • Motor Neurons / pathology
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Parkinson Disease / genetics*
  • Parkinson Disease / metabolism
  • Parkinson Disease / pathology
  • Phenotype
  • RNA Interference*
  • RNA, Untranslated / genetics*


  • Glial Cell Line-Derived Neurotrophic Factor
  • RNA, Untranslated