Neurodegeneration: role of noncoding RNA in molecular mechanisms

ILLU_0198_GG_Alzheimers_Disease (2)

Neurodegeneration is characterized by cumulative dysfunction and death of cells in selected areas of the nervous system. Neurodegenerative disorders typically present in old age with symptoms related to movement and cognition. The greatest burden of disease in the US, by number of individuals affected, is caused by Alzheimer’s disease (AD) (1). Characteristics of AD include memory loss, language difficulties and behavioral changes. Parkinson’s disease (PD), characterized by the loss of dopamine-producing neurons in the brain, is the second most common neurodegenerative disorder. Amyotrophic lateral sclerosis (ALS) affects motor neurons responsible for voluntary movement, eventually leading to loss of muscular control and muscular atrophy.

Although each disease is distinct, neurodegenerative disorders share many common features. They are often classified as diseases of aging. However, familial forms have an earlier age of onset and have provided significant insights into the molecular mechanisms of disease. Protein abnormalities, including misfolding, aggregation and aberrant localization, are common. Other shared hallmarks of neurodegenerative disease are oxidative stress and inflammation-induced neurotoxicity. Some diseases, such as Alzheimer’s and Parkinson’s, share overlapping genetic mutations.

Despite a wealth of knowledge, the cause of neurodegenerative disease is often unknown. Even in cases where a genetic basis for the disease is certain, such as SOD1 in some familial cases of ALS, the disease process is still a mystery. Noncoding RNAs are emerging as important players in the pathogenesis of neurodegenerative disease. Studies designed to elucidate the role of microRNA in neuronal maintenance utilized mouse models with conditional knockout of the RNA processing enzyme Dicer. Knockdown of Dicer expression in the midbrain of adult mice resulted in progressive loss of dopaminergic neurons and triggered neuronal apoptosis (2). Deletion of Dicer in other subpopulations of neuronal cells also results in neurodegeneration, behavioral changes or other hallmarks of motor neuron disease (3).

Long noncoding RNAs (lncRNA), transcripts >200 nucleotides long, have also been implicated in neural differentiation, maintenance and neurodegenerative disease (4). In AD, the BACE1 antisense transcript is upregulated relative to healthy controls, resulting in a net increase in BACE1 protein expression. Excess BACE1 results in an increase in Ab peptide, the main component of amyloid plaques. In Parkinson’s disease, RNA sequencing of patient leukocytes identified 13 lncRNAs with reduced expression relative to healthy controls, suggesting a role for lncRNA in the disease process (5). Although the functional role of noncoding RNA in neurodegenerative disease is not always easy to elucidate, evidence continues to suggest that noncoding RNAs are significant players in normal and pathologic neurobiology.

Interested in learning more about the molecular mechanisms of neurodegenerative disorders and the roles of noncoding RNAs in neurodegeneration?

Download our 3 webinar slide decks:

Part 1: Molecular mechanisms of neurodegeneration [Click here to download]

Part 2: The central roles of noncoding RNAs in neurodegenerative disorders [Click here to download]

Part 3: Circulating biomarkers for Alzheimer’s Disease [Click here to download]

  1. References:
  2. 1. Bertram, L. and Tanzi, R.E. (2005) The genetic epidemiology of neurodegenerative disease. J. Clin. Invest. 115, 1449. Link
  3. 2. Pang, X. et al. (2014) Dicer expression is essential for adult midbrain dopaminergic neuron maintenance and survival. Mol. Cell. Neurosci. 58, 22. Link
  4. 3. Gascon, E. and Gao, F.B. (2012) Cause or effect: misregulation of microRNA pathways in neurodegeneration. Front. Neurosci. 6, 48. Link
  5. 4. Wu, P. et al. (2013) Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. Brain Res. Bull. 97, 69. Link
  6. 5. Soreq, L. et al. (2014) Long non-coding RNA and alternative splicing modulations in Parkinson’s leukocytes identified by RNA sequencing. PLoS Comput. Biol. 10, e1003517. Link

 

Wei Cao, Ph.D.

Global Marketing Manager, Translational Sciences

Dr. Wei Cao joined QIAGEN in 2010 and currently leads the webinar program, presenting various topics on advanced techniques in biomedical research. She received her Ph.D. from Peking University in China in 2010, and conducted postdoctoral research at Weill Cornell Medical College in New York City. Before joining QIAGEN, Dr. Cao worked as a senior scientist in R&D in pharmaceutical and biotech, focusing on HIV, HCV and cancer drug discovery and development.

fangfangqi

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