4 research outputs found
UBA1: At the Crossroads of Ubiquitin Homeostasis and Neurodegeneration
Neurodegenerative diseases are a leading cause of disability and early death. A common feature of these conditions is disruption of protein homeostasis. Ubiquitin-like modifier activating enzyme 1 (UBA1), the E1 ubiquitin-activating enzyme, sits at the apex of the ubiquitin cascade and represents an important regulator of cellular protein homeostasis. Critical contributions of UBA1-dependent pathways to the regulation of homeostasis and degeneration in the nervous system are emerging, including specific disruption of UBA1 in spinal muscular atrophy (SMA) and Huntington's disease (HD). In this review we discuss recent findings that put UBA1 at the centre of cellular homeostasis and neurodegeneration, highlighting the potential for UBA1 to act as a promising therapeutic target for a range of neurodegenerative diseases
Morphological variability is greater at developing than mature mouse neuromuscular junctions
The neuromuscular junction (NMJ) is the highly specialised peripheral synapse formed between lower motor neuron terminals and muscle fibres. Postâsynaptic acetylcholine receptors (AChRs), which are found in high density in the muscle membrane, bind to acetylcholine released into the synaptic cleft of the NMJ, thereby enabling the conversion of motor action potentials to muscle contractions. NMJs have been studied for many years as a general model for synapse formation, development and function, and are known to be early sites of pathological changes in many neuromuscular diseases. However, information is limited on the diversity of NMJs in different muscles, how synaptic morphology changes during development, and the relevance of these parameters to neuropathology. Here, this crucial gap was addressed using a robust and standardised semiâautomated workflow called NMJâmorph to quantify features of preâ and postâsynaptic NMJ architecture in an unbiased manner. Five wholemount muscles from wildâtype mice were dissected and compared at immature (postânatal day, P7) and early adult (P31â32) timepoints. The interâmuscular variability was greater in mature postâsynaptic AChR morphology than that of the preâsynaptic motor neuron terminal. Moreover, the developing NMJ showed greater differences across muscles than the mature synapse, perhaps due to the observed distinctions in synaptic growth between muscles. Nevertheless, the amount of nerve to muscle contact was consistent, suggesting that pathological denervation can be reliably compared across different muscles in mouse models of neurodegeneration. Additionally, mature postâsynaptic endplate diameters correlated with fibre type, independently of muscle fibre diameter. Altogether, this work provides detailed information on healthy preâ and postâsynaptic NMJ morphology from five anatomically and functionally distinct mouse muscles, delivering useful reference data for future comparison with neuromuscular disease models