Table 1.

Summary of RAN proteins identified in neurologic disease.

Transcript	RAN protein	Protein accumulation in vivo
C9 ALS/FTD
Sense	GP	All C9 RNA protein are found as cytoplasmic or perinuclearaggregates in different brain regions of C9 ALS/FTD postmortem tissue, including frontal and motor cortex, hippocampus, dentate gyrus granular layer, cerebellar molecular layer and spinal cord of. In a C9 BAC transgenic mouse model with motor and neurodegenerative phenotype, PolyGlyAla accumulation increase with mouse age and phenotype. Individual C9 RAN proteins induce toxicity both in vitro and in vivo. Some of the C9-RAN mediated toxic mechanisms include alterations of the nucleocytoplasmic transport, ER stress, oxidative stress, stress granule formation, deficits in protein translation or DNA damage (26, 27,29,31,58,59,61–68,70–78,80–82).
	GR
	GA
Antisense	GP
	PR
	PA
FXTAS
Sense	PolyGly	PolyGly protein accumulates as nuclear and perinuclear aggregates in the frontal cortex and hippocampus of FXTAS patients, frequently colocalizimg with ubiquitin. A specific signal for polyGly protein is detected by Western blotting in lysates from FXTAS cerebellum. Colocalization between polyGly and ubiquitin is also detected in a FXTAS Drosophila model carrying 90 CGG repeats (32).
Antisense	PolyPro	Specific PolyPro intranuclear aggregates detected t in cortex, hippocampus, cerebellum, midbrain and pons from FXTAS brain tissue. These aggregates are mainly found un neurons and colocalize with Ubiquitin (90).
	PolyAla	Show a perinuclear and intranuclear accumulation in the neurons of FXTAS hippocampus and cortex, being also found in midbrain and pons. Intranuclear PolyAla inclusions are Ubiquitin positive (90).
FXPOI
Sense	PolyGly	FXPOI RAN PolyGly accumulates in the ovarian stromal cells of a FXPOI patient and FXTAS mice. Mice show and increase number of primordial follicules at 40 weeks and polyGly aggregates in the pituitary gland. PolyGly accumulates as intranuclear inclusions that are ubiquitin positive (104).
HD
Sense	polySer	All four proteins accumulate in grey matter regions and more abundantly in white matter regions of the striatum, frontal cortex and cerebellum of HD postmortem brain tissue. RAN positive show apoptotic and neuroinflammatory markers. HD-RAN proteins primarily show cytoplasmic, nuclear or perinuclear localization in neurons. In glial cells, the proteins predominantly show nuclear localization. Although both soluble and aggregated accumulation patters are frequently detected, polySer proteins accumulate as dotlike aggregates more frequently than polyAla, polyCys and polyLeu (33).
	polyAla
Antisense	PolyCys
	polyLeu
SCA8
Sense	PolySer	Detected in the cerebellum of SCA8 patients and in the cortex, hippocampus, brain stem and cerebellum of SCA8 BAC transfenic mice. In mice, polySer accumulates as dot-like agreggates in an age-dependent manner that correlates with the mouse motor dysfunction phenotype. PolySer preferentially accumulates in white matter regions that show demyelination and axonal degeneration (30).
Antisense	PolyAla	Accumulates in the cerebellum SCA8 mice and in the cerebellum of SCA8 patients. RAN SCA8 PolyAla is detected in the soma and dendrites of Purkinje cells (28).
DM1
Antisense	PolyGIn	Accumulates as nuclear aggregates in DM1 cardiac myocytes and leukocytes. PolyGIn inclusions are also found in myoblasts and skeletal muscle at low frequency. DM1 mice carrying 55CTG repeats show polyGIn staining in leukocytes in cardiac tissue (28).
DM2
Sense	LPAC	Primarily accumulates as small cytoplasmic or perinuclear aggregates in neurons, but also occasionally in glial cells, in brain regions showing abundant macrophages. Cortex, hippocampus and striatum are positive for LPAC acumulation (34).
Antisense	QAGR	Show nuclear accumulation that forms small agregates around the nuclear membrane. Preferentially accumulates in white matter regions displaying rarefaction of the fibers. QAGR is detected in DM2 cortex, hippocampus and striatum (34).
SCA31
Sense	WNGME	Detected in the eye imaginal discs of a SCA31 Drosophila model and in the cerebellum of SCA31 patients, where it accumulates as dot-like granules in the cell bodies and dendrites of Purkinje cells. In flies, WNGME levels correlate with increased eye degeneration (35).
FECD
Sense	PolyCys	Detected as nuclear immunostaining in the comeal endothelium of FECD patients carrying ≥ 55 repeats (36).
Antisense	PolyGIn	Detected by Western blot in fibroblast derived from FECD patients that are homozygous for the repeat expansion (36).