Astrocyte support is important for the compensatory potential of the nigrostriatal system neurons during early neurodegeneration. Issue 1 (9th December 2018)

• Record Type: Journal Article
• Authors: Kuter, Katarzyna; Olech, Łukasz; Głowacka, Urszula; Paleczna, Martyna
• Is Part Of: Journal of neurochemistry. Volume 148:Issue 1(2019)
• Page Start: 63
• Page End: 79
• Publication Date: 2018-12-09
• Subjects: brain fatty acid metabolism -- CPT1c -- glycogen -- ketone bodies -- neurodegeneration -- PGC‐1α; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14605
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Glial pathology precedes symptoms of Parkinson's disease and multiple other neurodegenerative diseases. Prolonged impairment of astrocytic functions could increase the vulnerability of dopaminergic neurons in the substantia nigra (SN), accelerate their degeneration and affect ability to compensate for partial degeneration at the presymptomatic stages of the disease. The aim of this study was to investigate the astrocyte depletion in the SN, its impact on the dopaminergic system functioning and multiple markers of energy metabolism during the early stages of neurodegeneration and compensation. We induced death of 30% of astrocytes by chronic infusion of fluorocitrate (FC) into the SN, simultaneously activating microglia response but sparing the dopaminergic neurons. The FC effect was reversible after toxin withdrawal. Dopaminergic neurons were killed by 6‐hydroxydopamine causing transient locomotor disability, reversed with time showing compensatory potential. Death of astrocytes diminished the capability of the dopaminergic system to compensate for the degeneration of neurons and caused a local energy deprivation by decreasing lactate and glycogen amount. Studied markers suggest a shift in the usage of energy substrates, via increased glycogenolysis and glycolysis markers, ketone bodies availability and fatty acid transport in remaining cells. Peroxisome proliferator‐activated receptor‐gamma coactivator 1α (PGC‐1alpha) and AMP‐activated protein kinase (AMPK), the energy sensors, showed different regulation between the cell‐types. Increased neuronal expression of carnitine palmitoyltransferase 1c could play a role in the adaptation to metabolic stress in response to glia dysfunction. Astrocyte energetic support is one of the essential factors for neuronal compensatory mechanisms of dopaminergic system and might have a leading role in the presymptomatic Parkinson's disease stages. Open science badges: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found athttps://cos.io/our-services/open-science-badges/ . Abstract : Prolonged impairment of astrocytic functions in substantia nigra diminished dopaminergic system capability to compensate for partial degeneration of neurons. It caused local energy deprivation, decreasing lactate and glycogen amount, promoting shift in the usage of energy substrates by increasing ketone bodies availability. Increased neuronal CPT1c and astrocytic CPT1a expression indicate upregulation of fatty acids metabolism. Regulator proteins PGC‐1α and AMPK play different roles in response to glia dysfunction. Open Science: This manuscript was awarded with the Open Materials Badge. For more information see:https://cos.io/our-services/open-science-badges/