Behavioural Neurology

Review Article

Molecular Mechanisms of Neurodegeneration Related to C9orf72 Hexanucleotide Repeat Expansion

Table 1

Summary of studies on the mechanisms by which C9orf72 repeat expansions cause neurodegeneration.


Reference	Molecular mechanism supported by the study			Experimental model
	Loss-of-function	Gain-of-function
	Loss-of-function	RNA-mediated gain-of-function	Protein-mediated gain-of-function

Renton et al. [15]		+		Human DNA Human brain tissue Cell culture

DeJesus-Hernandez et al. [14]	+	+		Human DNA Human brain tissue Cell culture

Gijselinck et al. [16]	+			Human brain tissue Human DNA

Fratta et al. [58]		+	+	Human DNA

Therrien et al. [52]	+			Caenorhabditis elegans

Belzil et al. [135]	+			Human brain tissue Cell culture

Gendron et al. [67]		+	+	Human DNA Human brain tissue Cell lines

Zu et al. [93]		+	+	Human brain tissue Human RNA Cell culture

Mizielinska et al. [68]		+		Human brain tissue

Lee et al. [70]		+		Human brain tissue Cell culture Zebrafish embryos Rat brain

Sareen et al. [71]		+		iPSC-derived neurons

Xu et al. [72]		+		Cell culture Drosophila

Lagier-Tourenne et al. [54]		+		Human brain tissue Cell culture

Donnelly et al. [69]		+		Human brain tissue Cell culture iPSC-derived neurons

Ciura et al. [53]	+			Zebrafish Human brain tissue Cell culture

Wen et al. [94]		+	+	Cell culture Drosophila

Liu et al. [50]		+	+	Human autopsy tissue Human DNA Cell culture

May et al. [138]			+	Human brain samples Cell culture

Zhang et al. [102]			+	Human brain samples Cell culture

Cooper-Knock et al. [73]		+		Human brain samples Cell culture

Su et al. [134]		+	+	Cell culture

Kwon et al. [95]			+	Cell culture

Haeusler et al [51]		+		Human brain tissue iPSC-derived neurons Cell culture

Mizielinska et al. [87]		+	+	Drosophila

Russ et al. [139]		+	+	Human DNA

Prudencio et al. [113]		+	+	Human brain tissue

Chew et al. [140]		+	+	Mouse model expressing 66 G4C2 repeats

Freibaum et al. [32]	+		+	Drosophila

Yang et al. [101]			+	Drosophila Human brain samples Cell culture iPSC-derived neurons

Jovičić et al. [33]			+	Yeast cells Cell culture

Yamakawa et al. [99]			+	Cell culture Mice brains

Hu et al. [141]		+		Cell culture

Gendron et al. [110]			+	Human brain samples

Tao et al. [98]			+	Cell culture

Tran et al. [86]			+	Drosophila iPSC-derived neurons Human brain tissue

Koppers et al. [55]		+	+	Conditional C9orf72 knockout mouse model

Cooper-Knock et al. [83]		+		Human brain tissue

Zhang et al. [31]		+	+	Drosophila iPSC-derived neurons Human brain tissue

Rossi et al. [84]		+		Cell culture

Cooper-Knock et al. [116]		+		Cell culture

Schweizer Burguete et al. [85]		+		Cell culture Drosophila iPSC-derived neurons

Liu et al. [92]		+	+	BAC mouse model of C9FTD/ALS

Kanekura et al. [96]			+	Human brain samples Cell culture

Boeynaems et al. [142]			+	Drosophila

Chang et al. [103]			+	Cell culture

Flores et al. [143]			+	Cell culture

Lin et al. [126]			+	Cell culture

Lopez-Gonzalez et al. [144]			+	iPSC-derived neurons

Liu et al. [145]	+			Human DNA and RNA

Dodd et al. [146]		+

Zhang et al. [147]			+	Mice that exhibit poly(GA) pathology

Westergard et al. [148]			+	iPSC-derived neurons Cell culture

Sellier et al. [36]	+			Cell culture Zebrafish

Mori et al. [149]		+	+	Human brain samples Cell culture

Gijselinck et al. [19]	+			Human DNA

Ugolino et al. [150]	+			C9orf72 knockout mice C9orf72 knockdown cell models

Lee et al. [125]			+	Drosophila Cell culture

O’Rourke et al. [40]		+	+	C9orf72 +/− and C9orf72 −/− mice

Atanasio et al. [56]		+	+	C9orf72-deficient mouse

Jiang et al. [91]		+	+	C9orf72 +/− and C9orf72 −/− mice Mice expressing BAC with the human expanded C9orf72 gene

Webster et al. [34]	+			Cell culture iNeurons (obtained by differentiation of iNPCs)

Ji et al. [151]	+			C9orf72 knockout mouse model Cell culture

Ohki et al. [152]			+	Zebrafish

Liu et al. [153]		+		Cell culture

Hu et al. [154]		+		Cell culture

Green et al. [155]			+	Cell culture

Schludi et al. [156]			+	Transgenic mice expressing codon-modified (GA)₁₄₉

Gupta et al. [157]			+	Cell culture

Khosravi et al. [158]			+	Cell culture

Shi et al. [159]			+	Cell culture

Saberi et al. [160]			+	Human brain samples

Kramer et al. [105]			+	Cell culture

Herranz-Martin et al. [161]		+	+	Mice that overexpress 10 or 102 interrupted G4C2 repeats

Zhou et al. [162]			+	Cell culture Human brain samples

Lehmer et al. [163]			+	Human CSF

Hautbergue et al. [82]		+	+	Drosophila Cell culture

Boeynaems et al. [100]			+	Cell culture

Maharjan et al. [39]	+	+	+	Cell culture

Moens et al. [88]		+	+	Drosophila

Cheng et al. [164]			+	Cell culture

Swinnen et al. [165]		+		Zebrafish

Shi et al. [59]	+		+	Cell culture iPSC-derived neurons Human brain samples

Simone et al. [137]		+	+	iPSC-derived neurons Drosophila

Tabet et al. [166]			+	Human brain sections Cell culture

Corrionero and Horvitz [167]	+			Caenorhabditis elegans

Zamiri et al. [168]		+		CD spectroscopy UV melting Gel electrophoresis

Swaminathan et al. [104]			+	Zebrafish

Yeh et al. [169]	+			Zebrafish

Meeter et al. [170]			+	Human brain samples
Nonaka et al. [171]			+	Cell culture

Frick et al. [29]	+			Human brain samples Cell culture C9orf72 knockout mice

BAC: bacterial artificial chromosome; CSF: cerebrospinal fluid; iNPCs: induced neural progenitor cells; iPSC: induced pluripotent stem cells. Studies investigating pathological mechanisms of C9orf72 HRE but not clearly supporting any of the three proposed disease mechanisms are not included in this table. Search for these studies was completed on May 20, 2018. The literature search was performed in Google Scholar using the keywords: “C9orf72”, “mechanism”, “pathological”, “loss-of-function”, “gain-of-function”, “haploinsufficiency”, “RNA foci”, and “DPR”. The literature search was conducted by two independent researchers.