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Mitochondria in Huntington’s Disease
Published in Abhai Kumar, Debasis Bagchi, Antioxidants and Functional Foods for Neurodegenerative Disorders, 2021
It was shown recently that huntingtin is involved in different mitophagy steps, promoting the physical proximity of different protein complexes during the initiation of mitophagy and recruiting mitophagy receptors essential for promoting the interaction between damaged mitochondria and the nascent autophagosome (Franco-Iborra et al., 2020). The presence of the polyQ tract in mutant huntingtin affects the formation of these protein complexes and determines the negative consequences of mutant huntingtin on mitophagy, leading to the accumulation of damaged mitochondria and an increase in oxidative stress. These outcomes contribute to further mitochondrial dysfunction and subsequently neurodegeneration in HD (Franco-Iborra et al., 2020). There is overwhelming evidence demonstrating oxidative damage in HD (for reviews see Browne and Beal, 2006; Johri and Beal, 2012b; Chandra and Johri, 2016): (i) Elevated markers of oxidative damage (hemeoxygenase, 3-nitrotyrosine, malondialdehyde (MDA)) in human HD striatum and cortex by immunohistochemistry (Browne et al., 1999); (ii) increased levels of MDA and 4-hydroxynonenal in HD patients using biochemical assays (Stoy et al., 2005); (iii) increased lipid peroxidation in plasma that correlates with degree of severity in patients with HD (Chen et al., 2007); (iv) increased global oxidative stress, a reduction in antioxidant systems, that correlates with disease stage in patients with HD (Tunez et al., 2011); (v) increased cytoplasmic lipofuscin and increased DNA fragmentation in HD patients where the latter correlates with CAG repeat length (Tellez-Nagel et al., 1974; Braak and Braak, 1992; Portera-Cailliau et al., 1995; Butterworth et al., 1998; Browne et al., 1999); (vi) oxidative modifications of Aldolase C, glial fibrillary acidic protein, tubulin, γ-enolase, and creatine kinase B in both striatum and cortex from HD patients (Sorolla et al., 2008); (vii) inability of mitochondria from striatal neurons of postmortem brains of HD patients to handle large Ca2+ loads (Tabrizi et al., 1999; Lim et al., 2008); and (viii) oxidation of mitochondrial enzymes (pyridoxal kinase and antiquitin 1) resulting in decreased catalytic activity in the striatum samples of HD patients, providing a link to the bioenergetic deficits observed in HD (Sorolla et al., 2010). Thus, excessive mitochondrial oxidative damage might lead to excessive mitochondrial fission and mitophagy in HD.
Neuro-Ophthalmic Literature Review
Published in Neuro-Ophthalmology, 2022
David A. Bellows, John J. Chen, Hui-Chen Cheng, Panitha Jindahra, Peter W. MacIntosh, Collin McClelland, Michael S. Vaphiades, Xiaojun Zhang
Autoantibody against CRX/CORD2, HSP60, and aldolase C were found in higher rates than in patients with RP and normal controls, while α-enolase and CAII were seen at equal rates. Antibodies against recoverin were found in three patients with autoimmune retinopathy, and not seen in normal controls or patients with RP. The area under the receiver operator characteristic curve was 0.531 for anti-recoverin, 0.479 for anti-α-enolase, 0.489 for anti-CAII, 0.737 for anti-CRX/CORD2, 0.637 for anti-HSP60, and 0.664 for anti-aldolase C. A higher number of retinal antibodies was associated with autoimmune retinopathy (≥4 antibodies were seen in 32.6% of patients with autoimmune retinopathy, 5% of patients with RP, and 3% of controls). A higher number of anti-retinal antibodies were slightly associated with photodisruption on optical coherence tomography and severe dysfunction on electroretinography.
Early loss of cerebellar Purkinje cells in human and a transgenic mouse model of Alzheimer’s disease
Published in Neurological Research, 2021
Kiran Chaudhari, Linshu Wang, Jonas Kruse, Ali Winters, Nathalie Sumien, Ritu Shetty, Jude Prah, Ran Liu, Jiong Shi, Michael Forster, Shao-Hua Yang
We determined the cerebellar Purkinje cells in the APPswe/PSEN1dE9 mouse model. When stained with Calbindin and DAPI, a trend in Purkinje cell loss (−18.82 %) at 5-month age compared to wild type and further loss (−8.69%) 8.5 months when compared to 5 month AD mice (Figure 2A & 2B, WT 5-month n = 3, AD 5 month n = 5, AD 8.5 month n = 4). When co-stained with Aldolase C and β3-tubulin, a strong trend of cerebellar Purkinje cell loss (−37.11%) was observed in 5 months old APPswe/PSEN1dE9 mice when compared with age-matched wild-type littermates (Supplementary Figure S1A & 1B, WT n = 4 for WT, n = 5 for AD, p = 0.06). Furthermore, the Purkinje cells in APPswe/PSEN1dE9 mice had significantly smaller soma size than wild-type littermates (Supplementary Figure S1C p < 0.05). No difference in the length of neurite branches per cell was found between transgenic AD mice and wild-type littermates (Supplementary Figure S1D).
Current techniques to accurately measure anti-retinal autoantibodies
Published in Expert Review of Ophthalmology, 2020
Based on findings in our laboratory we have generated panels of antigens for retinal autoimmune disorders. Retinal proteins are printed directly on a membrane and validated with serum that previously tested positive. The panels of reactive autoantigens were selected based on the AAb frequency as determined by Western blotting for AR, CAR, or MAR. Autoantigens selected for use in our panels include photoreceptor proteins (recoverin, retinal arrestin, Rab6, TULP1), heat shock proteins (HSP27 and HSP60), carbonic anhydrase II, α-tubulin, and glycolytic enzymatic proteins that are found in photoreceptor cells (α-enolase, aldolase C, glyceraldehyde 3-phosphate dehydrogenase, pyruvate kinase M2).