0428同步年報-2021-全

044 ACTIVITY REPORT 2021 Targeting ALS and FTD Disease-Related DNA Structures for Drug Discovery G4C2 repeat-expanded DNA motifs on the C9orf72 gene provide conducive structural features with considerable flexibility, serving as a "hotspot" for selective drug binding. The current study highlights the potential of metal- anthracene complexes to treat two important neurological diseases, Amyotrophic lateral sclerosis (ALS) and Frontotemporal dementia (FTD). A myotrophic lateral sclerosis (ALS) is a multisystem neurodegenerative disease involving loss of motor neurons in the brain and spinal cord, leading to paralysis, speech disorders and respiratory failure. Frontotemporal dementia (FTD) is another form of progressive neurological disease characterized by language and personality disorders and behavioral changes caused by the loss of neurons in the frontal and temporal lobes of the brain. These two disorders were previously thought to be independent and distinct neurological disorders because they are heterogeneous at the clinical and neuropathological levels. Because of our limited understanding of disease onset and progression, as well as molecular and genetic mechanisms, there is as yet no cure for ALS or FTD. In recent years, technological advances and a deeper understanding of the molecular basis of neurological diseases have led to mounting evidence that ALS and FTD share some common clinical and genetic features. The discovery in 2011 that the C9orf72 gene is the most commonly implicated gene causing ALS and FTD has led to a paradigm shift in viewing these disorders as “purely” cognitive or movement disorders. 1 It is now recognized that both these neurodegenerative disorders are caused by an abnormal expansion of a hexanucleotide DNA repeat sequence, GGGGCC (commonly referred to as the G4C2 repeat) ( Fig. 1 ). In patients with ALS or FTD, the length of abnormal expanded DNA repeats can range from 800 to > 4000, whereas in normal individuals this length remains at about 30 repeats. The abnormal DNA expansion on the C9orf72 gene leads to loss of C9orf72 protein function, and might also serve as a major source of toxic RNA and peptides that cause neuronal damage. 2,3 Most current drug development strategies for these diseases therefore focus on inhibiting the production of the corresponding toxic RNA or proteins in cells. Detailed studies of the genetic basis at the atomic level will help to provide new insight and hopefully develop effective treatments against ALS and FTD. Ming-Hon Hou (National Chung Hsing University) and his collaborators Yih-Chern Horng (National Changhua University of Education), Jin Peng (Emory University, USA) and Stephen Neidle (University College London, UK) have long been working on neurological disease research and drug development. Using X-ray crystallography, Hou's team analyzed the important structural features of DNA and analogous RNA-DNA hybrid duplexes containing the G4C2 hexanucleotide repeat motif associated with ALS and FTD and proposed that the G4C2 repeat double helix DNA structure can be used as a target for small molecules. 4 Elucidation of the complex crystal structure required a high-resolution X-ray facility, which was performed at NSRRC beamlines TPS 05A and TLS 15A1 . The team solved the crystal structures of the DNA duplex d(GTGGGCCGAC)/(GTCGGCCCAC) Fig. 1 : Schematic representation of mechanisms of ALS/FTD pathogenesis induced by abnormal G4C2 repeat expansions on the chromosome 9 open reading frame 72 (C9orf72). The signature -GGGCCG- sequence corresponding to the G4C2 motif is highlighted with a red color box. [Reproduced from Ref. 4]