A novel phenotype for the dynein heavy chain mutation Loa: Altered dendritic morphology, organelle density, and reduced numbers of trigeminal motoneurons

Abstract

Dynein, the retrograde motor protein, is essential for the transport of cargo along axons and proximal dendrites in neurons. The dynein heavy chain mutation, Loa, has been reported to cause degeneration of spinal motor neurons, as well as defects of spinal sensory proprioceptive neurons, but cranial nerve nuclei have received little attention. Here, we examined the number and morphology of neurons in cranial nerve nuclei of young, adult and aged heterozygous Loa mice, with focus on the trigeminal, facial, and trochlear motor nuclei, as well as the proprioceptive mesencephalic trigeminal nucleus. Using stereological counting techniques, we report a slowly progressive and significant reduction, to 75% of wildtype controls, in the number of large trigeminal motoneurons, while normal numbers were found for sensory mesencephalic trigeminal, and facial and trochlear motoneurons. The morphology of many surviving large trigeminal motoneurons was substantially altered, in particular the size and length of perpendicularly extending primary dendrites, but not those of facial or trochlear motoneurons. At the ultrastructural level, proximal dendrites of large trigeminal motoneurons, but not other neurons, were significantly depleted in organelle content such as polyribosomes and showed abnormal (vesiculated) mitochondria. These data indicate primary defects in trigeminal alpha motoneurons more than gamma motoneurons. Our findings expand the Loa heterozygote phenotype in two important ways: we reveal dendritic in addition to axonal defects or abnormalities, and we identify the Loa mutation as a mouse model for mixed motor-sensory loss when the entire neuraxis is considered, rather than a model primarily for sensory loss.

BORC/kinesin-1 ensemble drives polarized transport of lysosomes into the axon

“…It would thus be of interest to test if KIF1A and KIF1Bβ mediate lysosome transport in dendrites. Alternatively, lysosome transport in dendrites could be mediated by dynein, as shown in previous studies (20,33,70). Further studies will be needed to assess the relative contributions of different microtubule motors to lysosome transport in dendrites.…”

Cytoplasmic dynein: a key player in neurodegenerative and neurodevelopmental diseases

“…The phenotype of the Loa/+ mouse differs considerably between the cranial and the spinal levels of the neuraxis. -motoneuron loss in the trigeminal motor nucleus was already apparent at an early postnatal age and progressed only minimally with age [37]. These findings give rise to questions of how dynein dysfunction results in selective neural degeneration, especially selective motor neuron degeneration.…”

“…While our study suggested that Loa/+ mice also suffered from early-onset proprioceptive sensory neuropathy or possibly primary effects on the sensory neurons. A recent study by Wiggins [37], found that Loa/+ mice displayed deficits in both the motor and sensory nervous system. This argues against a model primarily involving sensory loss.…”

“…In fact, each factor functions during discrete developmental periods and target selection occurs at different time-points. For example, NT-3 signaling significantly affects neurons in the lumbar spinal cord, in contrast to those innervating the mastication muscles of the jaw [37,39]. Aberrant neurofilament accumulation in Loa/+ and Cra1/+ mice may explain the motor neu-ron degeneration as being the result of dynein-mediated dysfunction of transport [40].…”

Morphological changes and altered expression of antioxidant proteins in a heterozygous dynein mutant; a mouse model of spinal muscular atrophy

“…The heterozygous Loa/+ mice develop pathological features similar to the SMA-LED early onset: abnormal motor neuron innervation, decreased number of spinal cord ventral horn motor neurons, motor neuron degeneration, impaired coordination, abnormal grip strength, muscle spasms, accumulation of fat in tissues and abnormal mitochondrial morphology and function [7-10]. Typical pathological findings in heterozygous Loa/+ mice include early-onset degeneration of spinal motor neurons and proprioceptive sensory neuropathy, muscle spindle deficiency, neuromuscular junction defects, neuronal migration, alteration of axonal transport of cargoes, abnormalities due to alteration of the morphology of motor neurons and vacuolar mitochondria [8, 11-13]. It was proposed that such changes in morphology of mitochondria correlate with oxidative stress in other neurodegenerative diseases with imbalance between oxidant and antioxidant proteins [14-16].…”