TDP-43 and spinocerebellar ataxia type 31 (SCA31)
Spinocerebellar ataxia (SCA) is a progressive degenerative genetic disease that occurs in about 30 different forms, each of which can be considered a neurological condition in its own right. There are as many people diagnosed with spinocerebellar ataxia as there are people diagnosed with ALS. SCA is hereditary, progressive, degenerative and often fatal. Curiously for a disease whose origin is clearly genetic, there is no effective treatment on the market.
One recent publication alludes to the role of TDP-43 in certain neurodegenerative diseases. TDP-43 acts as an RNA chaperone against toxic proteins.
SCA can affect anyone at any age. Symptoms include non-cerebellar features, such as parkinsonism, chorea, pyramidalism, cognitive disorders, peripheral neuropathy, seizures, among others. As with other forms of ataxia, SCA frequently causes atrophy of the cerebellum, loss of fine coordination of muscle movements resulting in unstable and clumsy movement, and other symptoms.
As with ALS, the symptoms of ataxia vary by type and patient. In many cases, a person with ataxia retains full mental capacity but gradually loses physical control.
Unlike ALS, the causes of which are unclear, most types of ACS are caused by a recessive or dominant gene. In many cases, people do not know that they carry a relevant gene before having children begin to show signs of the disease.
Kinya Ishikawa and Yoshitaka Nagai were interested in spinocerebellar ataxia type 31 (SCA31), which is one of the dominant autosomal neurodegenerative disorders that shows progressive cerebellar ataxia as a cardinal symptom.
This disease is caused by a complex long pentanucleotide repeat of 2.5 to 3.8 kb (TGGAA), (TAGAA), (TAAAA) and (TAAAATAGAA) in an intron of the gene called BEAN1, which is expressed in the brain and associated with Nedd4.
By comparing various pentanucleotide repeats in this particular locus among the Japanese and Caucasian control populations, it was found that (TGGAA) was the only sequence correlated with SCA31.
This complex repetition also resides in the intron of another gene, TK2 (thymidine kinase 2), which is transcribed in the opposite direction, indicating that complex repetition is bidirectionally transcribed as non-coding repeats.
In the human brain with SCA31 variant (UGGAA), it was found that the BEAN1 transcript of the SCA31 mutation formed abnormal RNA structures called RNA foci in Purkinje cells of the cerebellum.
* By BrainsRusDC - Personal work, CC BY 4.0, https://commons.wikimedia.org/w/index.php?curid=64271015*
RNA reduction analysis subsequently revealed that (UGGAA) binds to the TDP-43, FUS and hnRNP A2 / B1 RNA binding proteins.
In fact, it has been found that TDP-43 co-localizes with RNA foci in human Purkinje SCA31 cells. To dissect the pathogenesis of (UGGAA) in SCA31, the authors generated SCA31-like transgenic fly models by overexpressing the pentanucleotide repeats of the SCA31 complex in Drosophila. They found that the toxicity of (UGGAA) depends on the length and level of expression and that it is attenuated by the co-expression of TDP-43, FUS and hnRNP A2 / B1. Further investigation revealed that TDP-43 improves toxicity (UGGAA) by directly correcting the abnormal structure of (UGGAA).
This led them to propose that TDP-43 act as an RNA chaperone against toxic substances (UGGAA) n. Further research on the role of RNA binding proteins as RNA chaperones could provide a new therapeutic strategy for SCA31, or even for other TDP-43 type proteopathies.
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