TY - JOUR
T1 - Absence of UCHL 1 function leads to selective motor neuropathy
AU - Genç, Bariş
AU - Jara, Javier H.
AU - Schultz, Megan C.
AU - Manuel, Marin
AU - Stanford, Macdonell J.
AU - Gautam, Mukesh
AU - Klessner, Jodi L.
AU - Sekerkova, Gabriella
AU - Heller, Daniel B.
AU - Cox, Gregory A.
AU - Heckman, Charles J.
AU - Didonato, Christine J.
AU - Özdinler, P. Hande
N1 - Publisher Copyright:
© 2016 American Neurological Association.
Copyright:
Copyright 2017 Elsevier B.V., All rights reserved.
PY - 2016/5/1
Y1 - 2016/5/1
N2 - Objective: The aim of this study was to investigate the role of ubiquitin C-terminal hydrolase-L1 (UCHL1) for motor neuron circuitry and especially in spinal motor neuron (SMN) health, function, and connectivity. Methods: Since mutations in UCHL1 gene leads to motor dysfunction in patients, we investigated the role of UCHL1 on SMN survival, axon health, and connectivity with the muscle, by employing molecular and cellular marker expression analysis and electrophysiological recordings, in healthy wild-type and Uchl1nm3419 (UCHL1-/-) mice, which lack all UCHL1 function. Results: There is pure motor neuropathy with selective degeneration of the motor, but not sensory axons in the absence of UCHL1 function. Neuromuscular junctions (NMJ) are impaired in muscle groups that are innervated by slow-twitch or fast-twitch SMN. However, unlike corticospinal motor neurons, SMN cell bodies remain intact with no signs of elevated endoplasmic reticulum (ER) stress. Interpretation: Presence of NMJ defects and progressive retrograde axonal degeneration in the absence of major SMN soma loss suggest that defining pathology as a function of neuron number is misleading and that upper and lower motor neurons utilize UCHL1 function in different cellular events. In line with findings in patients with mutations in UCHL1 gene, our results suggest a unique role of UCHL1, especially for motor neuron circuitry. SMN require UCHL1 to maintain NMJ and motor axon health, and that observed motor dysfunction in the absence of UCHL1 is not due to SMN loss, but mostly due to disintegrated circuitry.
AB - Objective: The aim of this study was to investigate the role of ubiquitin C-terminal hydrolase-L1 (UCHL1) for motor neuron circuitry and especially in spinal motor neuron (SMN) health, function, and connectivity. Methods: Since mutations in UCHL1 gene leads to motor dysfunction in patients, we investigated the role of UCHL1 on SMN survival, axon health, and connectivity with the muscle, by employing molecular and cellular marker expression analysis and electrophysiological recordings, in healthy wild-type and Uchl1nm3419 (UCHL1-/-) mice, which lack all UCHL1 function. Results: There is pure motor neuropathy with selective degeneration of the motor, but not sensory axons in the absence of UCHL1 function. Neuromuscular junctions (NMJ) are impaired in muscle groups that are innervated by slow-twitch or fast-twitch SMN. However, unlike corticospinal motor neurons, SMN cell bodies remain intact with no signs of elevated endoplasmic reticulum (ER) stress. Interpretation: Presence of NMJ defects and progressive retrograde axonal degeneration in the absence of major SMN soma loss suggest that defining pathology as a function of neuron number is misleading and that upper and lower motor neurons utilize UCHL1 function in different cellular events. In line with findings in patients with mutations in UCHL1 gene, our results suggest a unique role of UCHL1, especially for motor neuron circuitry. SMN require UCHL1 to maintain NMJ and motor axon health, and that observed motor dysfunction in the absence of UCHL1 is not due to SMN loss, but mostly due to disintegrated circuitry.
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U2 - 10.1002/acn3.298
DO - 10.1002/acn3.298
M3 - Article
C2 - 27231703
AN - SCOPUS:85010014906
SN - 2328-9503
VL - 3
SP - 331
EP - 345
JO - Annals of clinical and translational neurology
JF - Annals of clinical and translational neurology
IS - 5
ER -