Absence of UCHL 1 function leads to selective motor neuropathy
| Autor: | Macdonell J. Stanford, P. Hande Özdinler, Mukesh Gautam, Megan C. Schultz, Christine J. DiDonato, Gregory A. Cox, Daniel B. Heller, Jodi L. Klessner, Charles J. Heckman, Marin Manuel, Javier H. Jara, Barış Genç, Gabriella Sekerková |
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| Přispěvatelé: | Northwestern University Feinberg School of Medicine, The Jackson Laboratory [Bar Harbor] (JAX) |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
General Neuroscience Endoplasmic reticulum [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology Sensory system Degeneration (medical) Anatomy Motor neuron Biology 03 medical and health sciences Electrophysiology 030104 developmental biology 0302 clinical medicine medicine.anatomical_structure nervous system medicine Soma Neurology (clinical) Neuron Axon Neuroscience Research Articles 030217 neurology & neurosurgery ComputingMilieux_MISCELLANEOUS Research Article |
| Zdroj: | Annals of Clinical and Translational Neurology Annals of Clinical and Translational Neurology, Wiley, 2016, 3 (5), pp.331-345. ⟨10.1002/ACN3.298⟩ |
| ISSN: | 2328-9503 |
| DOI: | 10.1002/ACN3.298⟩ |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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