A031 Mitochondrial damage mapping in fibroblasts from a patient with a unique combination of Huntington’s disease, Alzheimer’s disease and multisystem atrophy

<h3></h3> Structural and functional impairment of neuronal cells is responsible for a spectrum of neurodegenerative diseases (ND). Although the molecular basis of ND differs, cellular and subcellular mechanisms of the pathology are usually similar to each other. A 70-year old woman with negative family history showed atypical course of confirmed late onset Huntington´s Disease (HD) with expressive mitochondrial impairment in cultivated skin fibroblasts (SF) started before accelerated HD clinical progression. HD suspicion was confirmed by genetic testing (17/40 CAG triplets). HD progression rapidly accelerated (urinary incontinence, neurogenic orthostatic hypotension, oedema of lower limbs, swallowing impairment, weight loss, memory and orientation difficulties) after one fall injury two years later. She died from terminal bronchopneumonia at the age of 74 years. Post mortem analysis in brain confirmed besides HD two additional sporadic neurodegenerations: fully evolved multisystem atrophy and Alzheimer´s disease. Changes in cristae architecture and mitochondrial swelling were detected in patient´s SF compared to controls. Similarly mitochondrial membranes modulating proteins were changed. Drp1 protein was slightly increased (117%), Opa1 reached only 51% of control amount. Dramatic decrease of subunits of mitochondrial energy metabolism enzymes was detected: SDH70, SDH30 (CII, Complex II) varied between 35% and 74% of control values and subunits NDUFA9 (CI) decreased to 6%, Core2 (CII) to 10%, Cox1 (CIV) to 14,5%. Subunit E1- α (PDH complex) was decreased to 14% of controls. Mitochondrial pathology in SF of our proband was significantly worse compared to the ten-member group of classical HD patients (Vanisova et al., 2022). <h3>Supported by</h3> AZV MZ ČR NU20-04-00136, Cooperatio program in Paediatrics and Neurosciences.