Motor deficit in a tauopathy model is induced by disturbances of axonal transport leading to dying-back degeneration and denervation of neuromuscular junctions.
Several neurodegenerative diseases are characterized by both cognitive and motor deficits associated with accumulation of tau aggregates in brain, brainstem, and spinal cord. The Tg30 murine tauopathy model expresses a human tau protein bearing two frontotemporal dementia with Parkinsonism linked to chromosome 17 pathogenic mutations and develops a severe motor deficit and tau aggregates in brain and spinal cord. To investigate the origin of this motor deficit, we analyzed the age-dependent innervation status of the neuromuscular junctions and mutant tau expression in Tg30 mice. The human transgenic tau was detected from postnatal day 7 onward in motoneurons, axons in the sciatic nerve, and axon terminals of the neuromuscular junctions. The development and maturation of neuromuscular junctions were not disrupted in Tg30 mice, but their maintenance was disturbed in adult Tg30 mice, resulting in a progressive and severe muscle denervation. This muscle denervation was associated with early electrophysiological signs of muscle spontaneous activities and histological signs of muscle degeneration. Early loss of synaptic vesicles in axon terminals preceding motor deficits, accumulation of Gallyas-positive aggregates, and cathepsin-positive vesicular clusters in axons in the sciatic nerve suggest that this denervation results from disturbances of axonal transport. This physiopathological mechanism might be responsible for motor signs observed in some human tauopathies, and for synaptic dysfunction resulting from alterations at the presynaptic level in these diseases.
Laboratory of Histology, Neuroanatomy, and Neuropathology, Neuroscience Institute, Université Libre de Bruxelles, Brussels, Belgium.
Emilie
E
Audouard
Laboratory of Histology, Neuroanatomy, and Neuropathology, Neuroscience Institute, Université Libre de Bruxelles, Brussels, Belgium.
Laura
L
Van Hees
Laboratory of Histology, Neuroanatomy, and Neuropathology, Neuroscience Institute, Université Libre de Bruxelles, Brussels, Belgium.
Valérie
V
Suain
Laboratory of Histology, Neuroanatomy, and Neuropathology, Neuroscience Institute, Université Libre de Bruxelles, Brussels, Belgium.
Zehra
Z
Yilmaz
Laboratory of Anatomy, Biomechanics and Organogenesis, Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium.
Luc
L
Poncelet
Laboratory of Histology, Neuroanatomy, and Neuropathology, Neuroscience Institute, Université Libre de Bruxelles, Brussels, Belgium.
Karelle
K
Leroy
Laboratory of Histology, Neuroanatomy, and Neuropathology, Neuroscience Institute, Université Libre de Bruxelles, Brussels, Belgium. Electronic address: jpbrion@ulb.ac.be.
Jean-Pierre
JP
Brion
D000818:Animals; D001370:Axonal Transport / Q000502:physiology*; D001369:Axons / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D003714:Denervation / Q000379:methods; D004195:Disease Models, Animal; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000473:pathology; D009469:Neuromuscular Junction / Q000473:pathology*; D013116:Spinal Cord / Q000473:pathology; D013572:Synaptic Vesicles / Q000378:metabolism; D024801:Tauopathies / Q000235:genetics / Q000473:pathology*