Membrane trafficking defects as determinants of motor neuron susceptibility and degeneration in ALS

Bradley J. Turner, Julie D. Atkin

Research output: Chapter in Book/Report/Conference proceedingChapterResearchpeer-review

Abstract

Amyotrophic lateral sclerosis (ALS) is characterised by motor neuron death and accumulation of ubiquitinated protein inclusions. Motor neurons are large-calibre and long distance projection excitatory cells with unusually high energetic, synthetic and transport demands required for maintenance and survival. These neurons are therefore likely to be uniquely susceptible to intracellular transport abnormalities in cell bodies and distal axons. Here, we review increasing evidence that motor neuron vulnerability in ALS may be conferred by defects in intracellular trafficking pathways specialised for these cells. Firstly, many of the genes implicated in familial forms of ALS encode molecular machinery or enzymes directly mediating intracellular transport. Secondly, these ALS gene products and additional constituents of trafficking pathways form core components of pathology in familial and sporadic disease. Lastly, defective membrane, vesicle, protein and mRNA transport features prominently and early in motor neuron degeneration in ALS models. We provide a systematic summary of ALS-linked proteins including ALS2, CHMP2B, FIG4, FUS, OPTN, p150Glued, SOD1, TDP-43, VAPB and VCP with respect to their localisation, function and dysfunction in intracellular trafficking pathways, such as anterograde and retrograde axonal transport, endoplasmic-Golgi, endosome-lysosome and nuclear transport. The role of molecular motor-linked proteins such as kinesin, dynein and neurofilaments in motor neurodegeneration will also be addressed. We propose that intracellular membrane trafficking defects affecting key neuronal functions, such as neurotransmission, extracellular signalling and synaptic activity, may be an early determinant of motor neuron loss and common denominator of potentially many ALS-linked proteins.

LanguageEnglish
Title of host publicationMotor Neuron Diseases
Subtitle of host publicationCauses, Classification and Treatments
EditorsBradley J. Turner, Julie B. Atkin
Place of PublicationNew York
PublisherNova Science Publishers
Pages39-74
Number of pages36
ISBN (Print)9781614701019
Publication statusPublished - 2012

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Nerve Degeneration
Amyotrophic Lateral Sclerosis
Motor Neurons
Membranes
Molecular Motor Proteins
Ubiquitinated Proteins
Dyneins
Kinesin
Intracellular Membranes
Axonal Transport
Cell Nucleus Active Transport
Intermediate Filaments
Endosomes
Protein Transport
Lysosomes
Synaptic Transmission
Genes
Axons
Membrane Proteins
Proteins

Cite this

Turner, B. J., & Atkin, J. D. (2012). Membrane trafficking defects as determinants of motor neuron susceptibility and degeneration in ALS. In B. J. Turner, & J. B. Atkin (Eds.), Motor Neuron Diseases: Causes, Classification and Treatments (pp. 39-74). New York: Nova Science Publishers.
Turner, Bradley J. ; Atkin, Julie D. / Membrane trafficking defects as determinants of motor neuron susceptibility and degeneration in ALS. Motor Neuron Diseases: Causes, Classification and Treatments. editor / Bradley J. Turner ; Julie B. Atkin. New York : Nova Science Publishers, 2012. pp. 39-74
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Turner, BJ & Atkin, JD 2012, Membrane trafficking defects as determinants of motor neuron susceptibility and degeneration in ALS. in BJ Turner & JB Atkin (eds), Motor Neuron Diseases: Causes, Classification and Treatments. Nova Science Publishers, New York, pp. 39-74.

Membrane trafficking defects as determinants of motor neuron susceptibility and degeneration in ALS. / Turner, Bradley J.; Atkin, Julie D.

Motor Neuron Diseases: Causes, Classification and Treatments. ed. / Bradley J. Turner; Julie B. Atkin. New York : Nova Science Publishers, 2012. p. 39-74.

Research output: Chapter in Book/Report/Conference proceedingChapterResearchpeer-review

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Turner BJ, Atkin JD. Membrane trafficking defects as determinants of motor neuron susceptibility and degeneration in ALS. In Turner BJ, Atkin JB, editors, Motor Neuron Diseases: Causes, Classification and Treatments. New York: Nova Science Publishers. 2012. p. 39-74