A039 Effects of mutant huntingtin and TDP-43 in the hypothalamus on the development of neuropathology and metabolic dysregulation
Year: 2024
Type: conference-paper
Abstract: Background Huntington’s disease (HD) and the amyotrophic lateral sclerosis (ALS)-frontotemporal dementia (FTD) disease spectrum share early features including metabolic, behavioral and sleep disturbances. Studies in both HD and ALS cases show hypothalamic pathology with selective loss of neurons expressing the emotion and metabolic neuropeptides hypocretin (orexin) and oxytocin. While the main pathological protein in HD is mutant huntingtin (mHTT), TAR DNA-binding protein 43 (TDP-43) pathology is also present and is the major pathological hallmark of ALS-FTD. We hypothesize that mHTT and TDP-43 cause hypothalamic dysfunction resulting in the development of neuropathology and metabolic dysregulation of HD and ALS-FTD. Aim To investigate the effects of hypothalamic mHTT and TDP-43 overexpression on neuropathology and metabolism. Methods Mice were bilaterally injected with adeno-associated viral vectors expressing mHTT, TDP-43 or green fluorescent protein into the hypothalamus. Body weight was monitored at either 6 or 10 weeks post-injection before sacrifice. Hypothalamic tissue was processed for immunohistochemical analysis to investigate potential effects on hypocretin- and oxytocin-expressing neurons as well as on general cell loss. Additionally, we assessed the presence of TDP-43 inclusions in the injected tissue as well as in the R6/2 HD mouse using immunohistochemistry. Results Mice overexpressing mHTT or TDP-43 increased in body weight. Furthermore, hypothalamic TDP-43 overexpression replicated neuropathology observed in ALS patients, namely hypothalamic atrophy and loss of neurons expressing hypocretin and oxytocin. Conclusions These results further support the role of hypothalamic involvement in HD and ALS-FTD and open up the possibility of shared pathogenic mechanisms between these disorders.
Institution: Lund University
Language: English
Subfield: Cellular and Molecular Neuroscience
Field: Neuroscience
Domain: Life Sciences
Open Access status: gold
OpenAlex ID: W4402373659