Ablation of cytoskeletal scaffolding proteins, Band 4.1B and Whirlin, leads to cerebellar purkinje axon pathology and motor dysfunction

Julia Saifetiarova, Manzoor Bhat

Research output: Contribution to journalArticle

Abstract

The cerebellar cortex receives neural information from other brain regions to allow fine motor coordination and motor learning. The primary output neurons from the cerebellum are the Purkinje neurons that transmit inhibitory responses to deep cerebellar nuclei through their myelinated axons. Altered morphological organization and electrical properties of the Purkinje axons lead to detrimental changes in locomotor activity often leading to cerebellar ataxias. Two cytoskeletal scaffolding proteins Band 4.1B (4.1B) and Whirlin (Whrn) have been previously shown to play independent roles in axonal domain organization and maintenance in myelinated axons in the spinal cord and sciatic nerves. Immunoblot analysis had indicated cerebellar expression for both 4.1B and Whrn; however, their subcellular localization and cerebellum-specific functions have not been characterized. Using 4.1B and Whrn single and double mutant animals, we show that both proteins are expressed in common cellular compartments of the cerebellum and play cooperative roles in preservation of the integrity of Purkinje neuron myelinated axons. We demonstrate that both 4.1B and Whrn are required for the maintenance of axonal ultrastructure and health. Loss of 4.1B and Whrn leads to axonal transport defects manifested by formation of swellings containing cytoskeletal components, membranous organelles, and vesicles. Moreover, ablation of both proteins progressively affects cerebellar function with impairment in locomotor performance detected by altered gait parameters. Together, our data indicate that 4.1B and Whrn are required for maintaining proper axonal cytoskeletal organization and axonal domains, which is necessary for cerebellum-controlled fine motor coordination.

LanguageEnglish (US)
JournalJournal of Neuroscience Research
DOIs
StateAccepted/In press - Jan 1 2018

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Cytoskeletal Proteins
Cerebellum
Axons
Pathology
Purkinje Cells
Maintenance
Cerebellar Nuclei
Spinal Nerves
Cerebellar Ataxia
Cerebellar Cortex
Axonal Transport
Sciatic Nerve
Locomotion
Gait
Organelles
Spinal Cord
Proteins
Learning
Neurons
Health

Keywords

  • axonal degeneration
  • Band 4.1B
  • cerebellum
  • motor coordination
  • myelinated axons
  • Purkinje neurons
  • whirlin

ASJC Scopus subject areas

  • Cellular and Molecular Neuroscience

Cite this

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title = "Ablation of cytoskeletal scaffolding proteins, Band 4.1B and Whirlin, leads to cerebellar purkinje axon pathology and motor dysfunction",
abstract = "The cerebellar cortex receives neural information from other brain regions to allow fine motor coordination and motor learning. The primary output neurons from the cerebellum are the Purkinje neurons that transmit inhibitory responses to deep cerebellar nuclei through their myelinated axons. Altered morphological organization and electrical properties of the Purkinje axons lead to detrimental changes in locomotor activity often leading to cerebellar ataxias. Two cytoskeletal scaffolding proteins Band 4.1B (4.1B) and Whirlin (Whrn) have been previously shown to play independent roles in axonal domain organization and maintenance in myelinated axons in the spinal cord and sciatic nerves. Immunoblot analysis had indicated cerebellar expression for both 4.1B and Whrn; however, their subcellular localization and cerebellum-specific functions have not been characterized. Using 4.1B and Whrn single and double mutant animals, we show that both proteins are expressed in common cellular compartments of the cerebellum and play cooperative roles in preservation of the integrity of Purkinje neuron myelinated axons. We demonstrate that both 4.1B and Whrn are required for the maintenance of axonal ultrastructure and health. Loss of 4.1B and Whrn leads to axonal transport defects manifested by formation of swellings containing cytoskeletal components, membranous organelles, and vesicles. Moreover, ablation of both proteins progressively affects cerebellar function with impairment in locomotor performance detected by altered gait parameters. Together, our data indicate that 4.1B and Whrn are required for maintaining proper axonal cytoskeletal organization and axonal domains, which is necessary for cerebellum-controlled fine motor coordination.",
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N2 - The cerebellar cortex receives neural information from other brain regions to allow fine motor coordination and motor learning. The primary output neurons from the cerebellum are the Purkinje neurons that transmit inhibitory responses to deep cerebellar nuclei through their myelinated axons. Altered morphological organization and electrical properties of the Purkinje axons lead to detrimental changes in locomotor activity often leading to cerebellar ataxias. Two cytoskeletal scaffolding proteins Band 4.1B (4.1B) and Whirlin (Whrn) have been previously shown to play independent roles in axonal domain organization and maintenance in myelinated axons in the spinal cord and sciatic nerves. Immunoblot analysis had indicated cerebellar expression for both 4.1B and Whrn; however, their subcellular localization and cerebellum-specific functions have not been characterized. Using 4.1B and Whrn single and double mutant animals, we show that both proteins are expressed in common cellular compartments of the cerebellum and play cooperative roles in preservation of the integrity of Purkinje neuron myelinated axons. We demonstrate that both 4.1B and Whrn are required for the maintenance of axonal ultrastructure and health. Loss of 4.1B and Whrn leads to axonal transport defects manifested by formation of swellings containing cytoskeletal components, membranous organelles, and vesicles. Moreover, ablation of both proteins progressively affects cerebellar function with impairment in locomotor performance detected by altered gait parameters. Together, our data indicate that 4.1B and Whrn are required for maintaining proper axonal cytoskeletal organization and axonal domains, which is necessary for cerebellum-controlled fine motor coordination.

AB - The cerebellar cortex receives neural information from other brain regions to allow fine motor coordination and motor learning. The primary output neurons from the cerebellum are the Purkinje neurons that transmit inhibitory responses to deep cerebellar nuclei through their myelinated axons. Altered morphological organization and electrical properties of the Purkinje axons lead to detrimental changes in locomotor activity often leading to cerebellar ataxias. Two cytoskeletal scaffolding proteins Band 4.1B (4.1B) and Whirlin (Whrn) have been previously shown to play independent roles in axonal domain organization and maintenance in myelinated axons in the spinal cord and sciatic nerves. Immunoblot analysis had indicated cerebellar expression for both 4.1B and Whrn; however, their subcellular localization and cerebellum-specific functions have not been characterized. Using 4.1B and Whrn single and double mutant animals, we show that both proteins are expressed in common cellular compartments of the cerebellum and play cooperative roles in preservation of the integrity of Purkinje neuron myelinated axons. We demonstrate that both 4.1B and Whrn are required for the maintenance of axonal ultrastructure and health. Loss of 4.1B and Whrn leads to axonal transport defects manifested by formation of swellings containing cytoskeletal components, membranous organelles, and vesicles. Moreover, ablation of both proteins progressively affects cerebellar function with impairment in locomotor performance detected by altered gait parameters. Together, our data indicate that 4.1B and Whrn are required for maintaining proper axonal cytoskeletal organization and axonal domains, which is necessary for cerebellum-controlled fine motor coordination.

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