Mutant three-repeat tau expression initiates retinal ganglion cell death through Caspase-2

NEUROBIOLOGY OF DISEASE

卷:152

Article

Ngolab, Jennifer¹  Canchi, Saranya^1,3  Rasool, Suhail^1,4  Elmaarouf, Abderrahman²  Thomas, Kimberly²  Sarsoza, Floyd^1,3  Grundman, Jennifer¹  Mante, Michael¹  Florio, Jazmin¹  Nandankar, Nimisha¹  Korouri, Shaina¹  Zago, Wagner²  Masliah, Eliezer⁵  Rissman, Robert A.^1,3 

[1] Univ Calif San Diego, Dept Neurosci, Sch Med, 9500 Gilman Dr,MTF 309,MC 0624, La Jolla, CA 92093 USA

[2] Prothena Biosci, San Francisco, CA 94080 USA

[3] Vet Affairs San Diego Healthcare Syst, San Diego, CA 92161 USA

[4] Amydis Inc, San Diego, CA 92121 USA

[5] NIA, Div Neurosci & Lab Neurogenet, NIH, Bethesda, MD 20892 USA

关键词: Retina;    Tau;    3 repeat tau;    Retinopathy;    tauopathy;   

DOI  :  10.1016/j.nbd.2021.105277

来源: Elsevier

【 摘 要 】

The microtubule-associated protein tau is implicated in multiple degenerative diseases including retinal diseases such as glaucoma; however, the way tau initiates retinopathy is unclear. Previous retinal assessments in mouse models of tauopathy suggest that mutations in four-repeat (4R) tau are associated with disease-induced retinal dysfunction, while shifting tau isoform ratio to favor three-repeat (3R) tau production enhanced photoreceptor function. To further understand how alterations in tau expression impact the retina, we analyzed the retinas of transgenic mice overexpressing mutant 3R tau (m3R tau-Tg), a model known to exhibit Pick?s Disease pathology in the brain. Analysis of retinal cross-sections from young (3 month) and adult (9 month) mice detected asymmetric 3R tau immunoreactivity in m3R tau-Tg retina, concentrated in the retinal ganglion and amacrine cells of the dorsal retinal periphery. Accumulation of hyperphosphorylated tau was detected specifically in the detergent insoluble fraction of the adult m3R tau-Tg retina. RNA-seq analysis highlighted biological pathways associated with tauopathy that were uniquely altered in m3R tau-Tg retina. The upregulation of transcript encoding apoptotic protease caspase-2 coincided with increased immunostaining in predominantly 3R tau positive retinal regions. In adult m3R tau-Tg, the dorsal peripheral retina of the adult m3R tau-Tg exhibited decreased cell density in the ganglion cell layer (GCL) and reduced thickness of the inner plexiform layer (IPL) compared to the ventral peripheral retina. Together, these data indicate that mutant 3R tau may mediate toxicity in retinal ganglion cells (RGC) by promoting caspase-2 expression which results in RGC degeneration. The m3R tau-Tg line has the potential to be used to assess tau-mediated RGC degeneration and test novel therapeutics for degenerative diseases such as glaucoma.