TY  - JOUR
A1  - Bieniussa, Linda
A1  - Kahraman, Baran
A1  - Skornicka, Johannes
A1  - Schulte, Annemarie
A1  - Voelker, Johannes
A1  - Jablonka, Sibylle
A1  - Hagen, Rudolf
A1  - Rak, Kristen
T1  - Pegylated insulin-like growth factor 1 attenuates hair cell loss and promotes presynaptic maintenance of medial olivocochlear cholinergic fibers in the cochlea of the progressive motor neuropathy mouse
JF  - Frontiers in Neurology
N2  - The progressive motor neuropathy (PMN) mouse is a model of an inherited motor neuropathy disease with progressive neurodegeneration. Axon degeneration associates with homozygous mutations of the TBCE gene encoding the tubulin chaperone E protein. TBCE is responsible for the correct dimerization of alpha and beta-tubulin. Strikingly, the PMN mouse also develops a progressive hearing loss after normal hearing onset, characterized by degeneration of the auditory nerve and outer hair cell (OHC) loss. However, the development of this neuronal and cochlear pathology is not fully understood yet. Previous studies with pegylated insulin-like growth factor 1 (peg-IGF-1) treatment in this mouse model have been shown to expand lifespan, weight, muscle strength, and motor coordination. Accordingly, peg-IGF-1 was evaluated for an otoprotective effect. We investigated the effect of peg-IGF-1 on the auditory system by treatment starting at postnatal day 15 (p15). Histological analysis revealed positive effects on OHC synapses of medial olivocochlear (MOC) neuronal fibers and a short-term attenuation of OHC loss. Peg-IGF-1 was able to conditionally restore the disorganization of OHC synapses and maintain the provision of cholinergic acetyltransferase in presynapses. To assess auditory function, frequency-specific auditory brainstem responses and distortion product otoacoustic emissions were recorded in animals on p21 and p28. However, despite the positive effect on MOC fibers and OHC, no restoration of hearing could be achieved. The present work demonstrates that the synaptic pathology of efferent MOC fibers in PMN mice represents a particular form of “efferent auditory neuropathy.” Peg-IGF-1 showed an otoprotective effect by preventing the degeneration of OHCs and efferent synapses. However, enhanced efforts are needed to optimize the treatment to obtain detectable improvements in hearing performances.
KW  - cochlea
KW  - microtubules
KW  - MOC fibers
KW  - hearing loss
KW  - pegylated insulin-like growth factor 1
KW  - outer hair cell (OHC)
KW  - motor neuropathy
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-276669
SN  - 1664-2295
VL  - 13
ER  - 
TY  - JOUR
A1  - Deng, Chunchu
A1  - Reinhard, Sebastian
A1  - Hennlein, Luisa
A1  - Eilts, Janna
A1  - Sachs, Stefan
A1  - Doose, Sören
A1  - Jablonka, Sibylle
A1  - Sauer, Markus
A1  - Moradi, Mehri
A1  - Sendtner, Michael
T1  - Impaired dynamic interaction of axonal endoplasmic reticulum and ribosomes contributes to defective stimulus-response in spinal muscular atrophy
JF  - Translational Neurodegeneration
N2  - Background: Axonal degeneration and defects in neuromuscular neurotransmission represent a pathological hallmark
in spinal muscular atrophy (SMA) and other forms of motoneuron disease. These pathological changes do not
only base on altered axonal and presynaptic architecture, but also on alterations in dynamic movements of organelles
and subcellular structures that are not necessarily reflected by static histopathological changes. The dynamic interplay
between the axonal endoplasmic reticulum (ER) and ribosomes is essential for stimulus-induced local translation
in motor axons and presynaptic terminals. However, it remains enigmatic whether the ER and ribosome crosstalk is
impaired in the presynaptic compartment of motoneurons with Smn (survival of motor neuron) deficiency that could
contribute to axonopathy and presynaptic dysfunction in SMA.

Methods: Using super-resolution microscopy, proximity ligation assay (PLA) and live imaging of cultured motoneurons
from a mouse model of SMA, we investigated the dynamics of the axonal ER and ribosome distribution and
activation.

Results: We observed that the dynamic remodeling of ER was impaired in axon terminals of Smn-deficient motoneurons.
In addition, in axon terminals of Smn-deficient motoneurons, ribosomes failed to respond to the brain-derived
neurotrophic factor stimulation, and did not undergo rapid association with the axonal ER in response to extracellular
stimuli.

Conclusions: These findings implicate impaired dynamic interplay between the ribosomes and ER in axon terminals
of motoneurons as a contributor to the pathophysiology of SMA and possibly also other motoneuron diseases.
KW  - spinal muscular atrophy
KW  - BDNF stimulation
KW  - dynamics of ribosomal assembly
KW  - presynaptic ER dynamics
Y1  - 2022
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-300649
SN  - 2047-9158
VL  - 11
IS  - 1
ER  -