Sex-Specific Early Retinal Dysfunction in Mutant TDP-43 Transgenic Mice

Article type: Research Article

Authors: Gao, Ju^a | Leinonen, Henri^b | Wang, Evan J.^c | Ding, Mao^a | Perry, George^d | Palczewski, Krzysztof^{e; f} | Wang, Xinglong^{a; c; *}

Affiliations: [a] Department of Pharmacology and Toxicology, University of Arizona, Tucson, AZ, USA | [b] School of Pharmacy, University of Eastern Finland, Kuopio, Finland | [c] Department of Pathology, Case Western Reserve University, Cleveland, OH, USA | [d] College of Sciences, University of Texas at San Antonio, San Antonio, TX, USA | [e] Department of Ophthalmology, Gavin Herbert Eye Institute, UCI, Irvine, CA, USA | [f] Department of Physiology and Biophysics, Chemistry and Molecular Biology and Biochemsitry, UCI, Irvine, CA, USA

Correspondence: [*] Correspondence to: Xinglong Wang, Department of Pharmacology & Toxicology, University of Arizona, 1703 E Mabel Street, Skaggs Bldg Rm 112, Tucson, AZ 85721, USA. Tel.: +1 520 626 5963; E-mail: xlwang@arizona.edu.

Abstract: Background:Increasing evidence has highlighted retinal impairments in neurodegenerative diseases. Dominant mutations in TAR DNA-binding protein 43 (TDP-43) cause amyotrophic lateral sclerosis (ALS), and the accumulation of TDP-43 in the cytoplasm is a pathological hallmark of ALS, frontotemporal dementia (FTD), and many other neurodegenerative diseases. Objective:While homozygous transgenic mice expressing the disease-causing human TDP-43 M337V mutant (TDP-43M337V mice) experience premature death, hemizygous TDP-43M337V mice do not suffer sudden death, but they exhibit age-dependent motor-coordinative and cognitive deficits. This study aims to leverage the hemizygous TDP-43M337V mice as a valuable ALS/FTD disease model for the assessment also of retinal changes during the disease progression. Methods:We evaluated the retinal function of young TDP-43M337V mice by full field electroretinogram (ERG) recordings. Results:At 3–4 months of age, well before the onset of brain dysfunction at 8 months, the ERG responses were notably impaired in the retinas of young female TDP-43M337V mice in contrast to their male counterparts and age-matched non-transgenic mice. Mitochondria have been implicated as critical targets of TDP-43. Further investigation revealed that significant changes in the key regulators of mitochondrial dynamics and bioenergetics were only observed in the retinas of young female TDP-43M337V mice, while these alterations were not present in the brains of either gender. Conclusions:Together our findings suggest a sex-specific vulnerability within the retina in the early disease stage, and highlight the importance of retinal changes and mitochondrial markers as potential early diagnostic indicators for ALS, FTD, and other TDP-43 related neurodegenerative conditions.

Keywords: Alzheimer’s disease, amyotrophic lateral sclerosis, frontotemporal dementia, mitochondrial dynamics, OXPHOS, retina, sex differences, TDP-43

DOI: 10.3233/JAD-231102

Journal: Journal of Alzheimer's Disease, vol. 97, no. 2, pp. 927-937, 2024