title: Brain-specific knockdown of miR-29 results in neuronal cell death and ataxia in mice.
abstract: Several microRNAs have been implicated in neurogenesis, neuronal differentiation, neurodevelopment, and memory. Development of miRNA-based therapeutics, however, needs tools for effective miRNA modulation, tissue-specific delivery, and in vivo evidence of functional effects following the knockdown of miRNA. Expression of miR-29a is reduced in patients and animal models of several neurodegenerative disorders, including Alzheimer's disease, Huntington's disease, and spinocerebellar ataxias. The temporal expression pattern of miR-29b during development also correlates with its protective role in neuronal survival. Here, we report the cellular and behavioral effect of in vivo, brain-specific knockdown of miR-29. We delivered specific anti-miRNAs to the mouse brain using a neurotropic peptide, thus overcoming the blood-brain-barrier and restricting the effect of knockdown to the neuronal cells. Large regions of the hippocampus and cerebellum showed massive cell death, reiterating the role of miR-29 in neuronal survival. The mice showed characteristic features of ataxia, including reduced step length. However, the apoptotic targets of miR-29, such as Puma, Bim, Bak, or Bace1, failed to show expected levels of up-regulation in mice, following knockdown of miR-29. In contrast, another miR-29 target, voltage-dependent anion channel1 (VDAC1), was found to be induced several fold in the hippocampus, cerebellum, and cortex of mice following miRNA knockdown. Partial restoration of apoptosis was achieved by down-regulation of VDAC1 in miR-29 knockdown cells. Our study suggests that regulation of VDAC1 expression by miR-29 is an important determinant of neuronal cell survival in the brain. Loss of miR-29 results in dysregulation of VDAC1, neuronal cell death, and an ataxic phenotype.
authors: CSIR-Institute of Genomics and Integrative Biology, Delhi-110020, India.
authors: Reema
authors: R
authors: Roshan
authors: CSIR-Institute of Genomics and Integrative Biology, Delhi-110020, India.
authors: Shruti
authors: S
authors: Shridhar
authors: CSIR-Institute of Genomics and Integrative Biology, Delhi-110020, India.
authors: Mayuresh A
authors: MA
authors: Sarangdhar
authors: CSIR-Institute of Genomics and Integrative Biology, Delhi-110020, India.
authors: Arpita
authors: A
authors: Banik
authors: CSIR-Institute of Genomics and Integrative Biology, Delhi-110020, India.
authors: Mrinal
authors: M
authors: Chawla
authors: CSIR-Institute of Genomics and Integrative Biology, Delhi-110020, India.
authors: Manali
authors: M
authors: Garg
authors: CSIR-Institute of Genomics and Integrative Biology, Delhi-110020, India.
authors: Vijay P A L
authors: VP
authors: Singh
authors: CSIR-Institute of Genomics and Integrative Biology, Delhi-110020, India.
authors: Beena
authors: B
authors: Pillai
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001259:Ataxia / Q000235:genetics*; D001483:Base Sequence; D001921:Brain / Q000378:metabolism*; D016923:Cell Death / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D055785:Gene Knockdown Techniques; D006023:Glycoproteins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D009928:Organ Specificity / Q000235:genetics; D010446:Peptide Fragments / Q000737:chemistry / Q000378:metabolism; D010641:Phenotype; D034741:RNA, Small Interfering / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014764:Viral Proteins / Q000737:chemistry / Q000378:metabolism; D050995:Voltage-Dependent Anion Channel 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D006023:Glycoproteins; D010446:Peptide Fragments; D034741:RNA, Small Interfering; D014764:Viral Proteins; C583075:rabies virus glycoprotein peptide; D050995:Voltage-Dependent Anion Channel 1
keywords: VDAC1; ataxia; microRNA; neurodegeneration