Rossor, A. M. | bioRxiv Science

bioRxiv2022

MPZ-T124M mouse model replicates human axonopathy and suggest alteration in axo-glia communication

Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 (P0T124M) causes axonal neuropathy (CMT2J) with little to no myelin damage. This disease provides an excellent paradigm to understand how myelinating glia support axons independently from myelin. To study this, we generated targeted knock-in P0T124M mutant mice, a genetically authentic model of T124M-CMT2J neuropathy. Similar to patients, these mice develop axonopathy between 2 and 12 months of age, characterized by impaired motor performance, normal nerve conduction velocities but reduced compound motor action potential amplitudes, and axonal damage with only minor compact myelin modifications. Mechanistically, we detected metabolic changes that could lead to axonal degeneration, and prominent alterations in non-compact myelin domains such as paranodes, Schmidt-Lanterman incisures, and gap junctions, implicated in Schwann cell-axon communication and axonal metabolic support. Finally, we document perturbed mitochondrial size and distribution along P0T124M axons suggesting altered axonal transport. Our data suggest that Schwann cells in P0T124M mutant mice cannot provide axons with sufficient trophic support, leading to reduced ATP biosynthesis and axonopathy. In conclusion, the P0T124M mouse model faithfully reproduces the human neuropathy and represents a unique tool for identifying the molecular basis for glial support of axons.

neuroscience↗

bioRxiv2019

Loss of BICD2 in muscle drives motor neuron loss in a developmental form of spinal muscular atrophy

BICD2 is a key component of the dynein/dynactin motor complex. Autosomal dominant mutations in BICD2 cause Spinal Muscular Atrophy Lower Extremity Predominant 2 (SMALED2), a developmental disease of motor neurons. In this study we sought to examine the motor neuron phenotype of conditional Bicd2-/- mice. Bicd2-/- mice show a significant reduction in the number of motor axons of the L4 ventral root compared to wild type mice. Muscle-specific knockout of Bicd2, but not motor neuron-specific Bicd2 loss, results in a reduction in L4 ventral axons comparable to global Bicd2-/- mice. Rab6, a small GTPase required for the sorting of secretory vesicles from the TGN to the plasma membrane is a major binding partner of BICD2. We therefore examined the secretory pathway in SMALED2 patient fibroblasts and demonstrated impaired flow of constitutive secretory cargoes. Together, these data indicate that BICD2 loss from muscles is a major driver of non-cell autonomous pathology with important implications for future therapeutic approaches to SMALED2. SummaryMissense mutations in the cargo adaptor protein BICD2 cause SMALED2, a developmental disease of motor neurons. In this study, the authors show that BICD2 mutations cause motor neuron loss by a non-cell autonomous mechanism determining a disabling impairment of muscle function.

neuroscience↗