Neurodegeneration in a transgenic mouse model of multiple system atrophy is associated with altered expression of oligodendroglial-derived neurotrophic factors.
Multiple system atrophy (MSA) is a neurodegenerative disorder characterized by striatonigral degeneration and olivo-pontocerebellar atrophy. Neuronal degeneration is accompanied by primarily oligodendrocytic accumulation of alpha-synuclein (alphasyn) as opposed to the neuronal inclusions more commonly found in other alpha-synucleinopathies such as Parkinson's disease. It is unclear how alphasyn accumulation in oligodendrocytes may lead to the extensive neurodegeneration observed in MSA; we hypothesize that the altered expression of oligodendrocyte-derived neurotrophic factors by alphasyn may be involved. In this context, the expression of a number neurotrophic factors reportedly expressed by oligodendrocytes [glial-derived neurotrophic factor (GDNF), brain-derived neurotrophic factor (BDNF), and insulin-like growth factor 1 (IGF-1), as well as basic fibroblast growth factor 2 (bFGF2), reportedly astrocyte derived] were examined in transgenic mouse models expressing human alphasyn (halphasyn) under the control of either neuronal (PDGFbeta or mThy1) or oligodendrocytic (MBP) promoters. Although protein levels of BDNF and IGF-1 were altered in all the alphasyn transgenic mice regardless of promoter type, a specific decrease in GDNF protein expression was observed in the MBP-halphasyn transgenic mice. Intracerebroventricular infusion of GDNF improved behavioral deficits and ameliorated neurodegenerative pathology in the MBP-halphasyn transgenic mice. Consistent with the studies in the MBP-halphasyn transgenic mice, analysis of GDNF expression levels in human MSA samples demonstrated a decrease in the white frontal cortex and to a lesser degree in the cerebellum compared with controls. These results suggest a mechanism in which alphasyn expression in oligodendrocytes impacts on the trophic support provided by these cells for neurons, perhaps contributing to neurodegeneration.
Ubhi
Kiren
K
Department of Neurosciences, University of California, San Diego, School of Medicine, La Jolla, California 92093-0624, USA.
Rockenstein
Edward
E
Mante
Michael
M
Inglis
Chandra
C
Adame
Anthony
A
Patrick
Christina
C
Whitney
Kristen
K
Masliah
Eliezer
E
D000368:Aged; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000008:administration & dosage; D006801:Humans; D007276:Injections, Intraventricular; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019578:Multiple System Atrophy / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000188:drug therapy* / Q000473:pathology; D009413:Nerve Fibers, Myelinated / Q000378:metabolism; D009414:Nerve Growth Factors / Q000378:metabolism*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000187:drug effects / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051844:alpha-Synuclein / Q000235:genetics
D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D051844:alpha-Synuclein
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