Details

Autor(en) / Beteiligte

• Carmen-Orozco, Rogger P
• Tsao, William
• Ye, Yingzhi
• Sinha, Irika R
• Chang, Koping
• Trinh, Vickie T
• Chung, William
• Bowden, Kyra
• Troncoso, Juan C
• Blackshaw, Seth
• Hayes, Lindsey R
• Sun, Shuying
• Wong, Philip C
• Ling, Jonathan P

Titel

Elevated nuclear TDP-43 induces constitutive exon skipping

Ist Teil von

• Molecular neurodegeneration, 2024-06, Vol.19 (1), p.45-17

Ort / Verlag

England: BioMed Central Ltd

Erscheinungsjahr

2024

Quelle

MEDLINE

Beschreibungen/Notizen

• Cytoplasmic inclusions and loss of nuclear TDP-43 are key pathological features found in several neurodegenerative disorders, suggesting both gain- and loss-of-function mechanisms of disease. To study gain-of-function, TDP-43 overexpression has been used to generate in vitro and in vivo model systems. We analyzed RNA-seq datasets from mouse and human neurons overexpressing TDP-43 to explore species specific splicing patterns. We explored the dynamics between TDP-43 levels and exon repression in vitro. Furthermore we analyzed human brain samples and publicly available RNA datasets to explore the relationship between exon repression and disease. Our study shows that excessive levels of nuclear TDP-43 protein lead to constitutive exon skipping that is largely species-specific. Furthermore, while aberrant exon skipping is detected in some human brains, it is not correlated with disease, unlike the incorporation of cryptic exons that occurs after loss of TDP-43. Our findings emphasize the need for caution in interpreting TDP-43 overexpression data and stress the importance of controlling for exon skipping when generating models of TDP-43 proteinopathy.