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Post-symptomatic Delivery of Brain Derived Neurotrophic Factor (BDNF) Ameliorates Spinocerebellar Ataxia Type 1 (SCA1) Pathogenesis

Authors
  • Sheeler, Carrie1
  • Rosa, Juao-Guilherme1
  • Borgenheimer, Ella1
  • Mellesmoen, Aaron1
  • Rainwater, Orion2
  • Cvetanovic, Marija1, 3
  • 1 Department of Neuroscience, University of Minnesota, 321 Church Street SE, Minneapolis, MN 55455, USA
  • 2 Department of Lab Medicine and Pathology, University of Minnesota, 420 Delaware Street SE, Minneapolis 55455, USA
  • 3 Street SE, Minneapolis, MN 55455, USA
Type
Published Article
Journal
Cerebellum (London, England)
Publication Date
Jan 04, 2021
Volume
20
Issue
3
Pages
420–429
Identifiers
DOI: 10.1007/s12311-020-01226-3
PMID: 33394333
PMCID: PMC8217121
Source
PubMed Central
Keywords
Disciplines
  • Article
License
Unknown

Abstract

Spinocerebellar ataxia type 1 (SCA1) is a fatal neurodegenerative disease caused by an abnormal expansion of CAG repeats in the Ataxin1 ( ATXN1 ) gene. SCA1 is characterized by motor deficits, cerebellar neurodegeneration, gliosis and gene expression changes. Expression of brain derived neurotrophic factor (BDNF), growth factor important for the survival and function of cerebellar neurons is decreased in ATXN1[82Q] mice, the Purkinje neuron specific transgenic mouse model of SCA1. As this decrease in BDNF expression may contribute to cerebellar neurodegeneration we tested whether delivery of extrinsic human BDNF via osmotic Alzet pumps has a beneficial effect on disease severity in this mouse model of SCA1. Additionally, to test the effects of BDNF on established and progressing cerebellar pathogenesis and motor deficits we delivered BDNF post-symptomatically. We have found that post-symptomatic delivery of extrinsic BDNF ameliorated motor deficits, and cerebellar pathology (i.e. dendritic atrophy of Purkinje cells, and astrogliosis) indicating therapeutic potential of BDNF even after the onset of symptoms in SCA1.However, BDNF did not alter Purkinje cell gene expression changes indicting that certain aspects of disease pathogenesis cannot be ameliorated/slowed down with BDNF and that combinational therapies may be needed.

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