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Ann Clin Transl Neurol. 2016 Mar 7;3(5):331-45. doi: 10.1002/acn3.298. eCollection 2016 May.

Absence of UCHL 1 function leads to selective motor neuropathy.

Author information

1
Department of Neurology and Clinical Neurological Sciences Northwestern University, Feinberg School of Medicine Chicago Illinois USA.
2
Department of Physiology Northwestern University, Feinberg School of Medicine Chicago Illinois USA; UMR 8119 CNRS/Paris Descartes University Paris France.
3
Department of Physiology Northwestern University, Feinberg School of Medicine Chicago Illinois USA.
4
The Jackson Laboratory Bar Harbor Maine USA.
5
Department of Medicine and Rehabilitation Northwestern University Feinberg School of Medicine Chicago Illinois USA; Department of Physical Therapy and Movement Sciences at Northwestern University Feinberg School of Medicine Chicago Illinois USA.
6
Department of Pediatrics Feinberg School of Medicine, Northwestern University Chicago Illinois USA; Human Molecular Genetics Program Ann & Robert H. Lurie Children's Hospital of Chicago Research Center Chicago Illinois USA.
7
Department of Neurology and Clinical Neurological Sciences Northwestern University, Feinberg School of Medicine Chicago Illinois USA; Robert H. Lurie Cancer Center Northwestern University Chicago Illinois USA; Cognitive Neurology and Alzheimer's Disease Center Northwestern University Chicago Illinois USA.

Abstract

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 Uchl1 (nm3419) (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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