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Molecular mechanisms of

amyotrophic lateral sclerosis


Funded by a grant from MT Pharma America, Inc.
Philip Van Damme, Ludo Van Den Bosch and Wim Robberecht
Amyotrophic lateral sclerosis (ALS) is a fatal, neurodegenerative disorder that primarily as in 5–10% of patients with sporadic ALS. The affected genes are involved in various
affects the motor system, resulting in progressive muscle weakness and paralysis. In cellular functions, pointing to a large variety of possible disease mechanisms that could
almost 90% of patients, the cause of ALS remains enigmatic, and most of our current lead to selective motor neuron degeneration. In this Poster, we provide an overview of
understanding of ALS is based on its genetics and neuropathology. The disease-causing the genetic causes of ALS and risk factors, and link these to the specific characteristics
gene mutation has been identified in the majority of patients with familial ALS, as well of motor neurons and to the most important pathogenic mechanisms.

a Impaired proteostasis Disturbance of stress b Disturbed RNA metabolism and RBPs c Nucleocytoplasmic d Cytoskeletal and axon-transport defects
ALS usually has a focal onset and spreads throughout the motor transport defects
Shedding granule dynamics Impaired actin Impaired
system, which explains the relentless progressive character of the mRNA Depletion of RBPs
and possible RBP polymerisation Axon cargo binding
disease and is suggestive of an underlying ‘prion-like’ spreading cell–cell
due to binding to
Protein repeat RNAs
mechanism. In some patients, degeneration extends to the frontal propagation aggregation Actin Tubulin Cargo
and anterior temporal lobes, giving rise to executive dysfunction, Inhibition of DNA Repeat Inhibition of destabilization
language impairments, behavioural changes and/or frontotemporal Aberrant transcription RNA transport by Motor DCTN1
autophagosomal Interference with aberrantly protein
dementia. Despite being uniformly fatal, ALS is associated with miRNA generation Actin monomer Tubulin
Misfolded clearance Defective generated
considerable variation in the age at onset, rate of disease splicing and silencing Nucleus proteins
protein Lysosome Stress granule Disrupted
progression, relative upper versus lower motor neuron involvement Negative effect on
pre-mRNA RNA transport and cytoskeleton Microtubule
and the degree of frontotemporal involvement. ALS is also linked Mislocalized
protein local translation Neurofilament Axon-transport defects
with considerable genetic heterogeneity: more than 20 genes have Inhibition of
been linked to ALS to date (table 1). Even in families with a Phagophore Aberrantly transport
generated Nucleus by repeat RNAs Accumulation of
monogenetic cause of ALS, the disease presentation is highly neurofilaments Axon
protein retraction
variable, suggestive of the existence of disease-modifying factors. Insufficient in axons
capacity of ER
The ALS disease process is characterized by axonal retraction and proteasome
subsequent loss of the cell bodies of upper and lower motor neurons. In f Vesicle-transport defects Secretory vesicle
most individuals with this disease, the degenerating neurons are Proteasome Nuclear
Repeat Decreased
characterized by cytoplasmic, ubiquitin-containing inclusions in which pore neurotransmitter
ER stress complex RNA Nucleus
TDP43 is present. Moreover, the affected motor neurons are surrounded release
Endosome–
by reactive astrocytes and microglia, and oligodendroglial function is Proposed disease mechanisms lysosome
Golgi
compromised. These cells clearly contribute to the disease process, and pathway
ALS is thus considered a non-cell-autonomous disease.
As illustrated (main figure), many different mechanisms have been Golgi Disturbed regulation
proposed to drive ALS pathogenesis. For at least some of these, it of vesicle fusion
e Impaired DNA repair
remains to be established whether the disturbances are involved in the
Oxidative stress and other
disease mechanism or are a secondary consequence of the disease Nuclear or insults induce single- and
process. Further research is necessary to clarify this issue. mitochondrial DNA double-strand breaks
The cornerstone of ALS treatment remains multidisciplinary care, Mitochondrion
including nutritional and respiratory support and symptom Dendrite
management. The only approved drug for ALS is riluzole, which Nucleus
presumably has an anti-excitotoxic mode of action, but the survival
benefit of this drug is limited. Future therapeutic strategies might Impaired DNA ER Axon
repair mechanisms
Cell death j Oligodendrocyte dysfunction
involve the development of therapies that directly regulate the
expression of the mutated genes or modulate the different proposed Degeneration of
Oligodendrocyte oligodendrocytes
pathogenic mechanisms (main figure).
Motor neuron
Lactate
Axon Myelin
Table 1 | Genetics of ALS
↓ ATP ↓ Lactate ↓ MCT1
Gene Pathogenic pathways g Excitotoxicity
Frequent Presynaptic
C9orf72* a–c,f,g neuron Astrocyte i Neuroinflammation and astrogliosis MCT1
Reduced support
FUS* a,b,e,g Increased neuronal Pro-inflammatory TH2 Treg for axons NG2 cell
SOD1* a,d,g–j excitability drives h Mitochondrial dysfunction factors Failure to
increased glutamate Mitochondrial TH1 replace mature
TARDBP* ‡
a,b,h release Apoptosis outer Astrocyte oligodendrocytes
Less frequent or in some cases associated with atypical ALS membrane
ALS2*, CHMP2B*, UNC13A§ and VAPB* f mPTP
Glutamate
ANG*, ATXN2, SETX*, ELP3§ b CD8
Ca2+ Intermembrane Microglial cell
HNRNPA1/A2/B1 and MATR3
EAAT2
space Determinants of motor neuron vulnerability
C21ORF2 and NEK1 e NMDAR AMPAR
↑ Ca2+ • Large size
CCNF, FIG4, OPTN*, SIGMAR1, a ↑ ROS ↓ ATP Neuroprotective Neurotoxic Neuroprotective Neurotoxic
Presence of highly Loss of astrocytic • Fast fatiguable motor units
SQSTM1, UBQLN2*, TBK1* and VCP* Ca2+-permeable EAAT2 impairs factors factors factors factors • Low GluR2 expression
↑ Ca2+ VEGF IL-6
CHCHD10 h AMPARs glutamate ROS IL-10 IL-2β • Low Ca2+ buffering
reuptake NO TGFβ ROS
DAO g Interference with GDNF BDNF IL-4 TNF • High EPHA4 expression
↑ ROS ↑ Toxic respiratory chain NO
DCTN1, NEFH, PRPH, TUBA4A, SPG11* d enzymes • Low IGF2 expression
Motor neuron Mitochondrial function
and PFN1* Neuron • High MMP9 expression
respiratory chain
GLE1 c Cell death Cell death • Low osteopontin expression
*Segregation of mutation with the disease in several families. ‡Encodes TDP43. §SNP association.
Mitochondrial inner membrane

Abbreviations MCT1, monocarboxylate transporter 1; miRNA, microRNA; MMP9, matrix metallo- Affiliations References 6. Boeynaems, S. et al. Inside out: the role of nucleocytoplasmic transport in project (Grant agreement No: 259867). P.V.D. holds a senior clinical
proteinase 9; mPTP, mitochondrial permeability transition pore; NEFH, neurofilament ALS and FTLD. Acta Neuropathol. 132, 159–173 (2016). investigatorship of FWO-Vlaanderen. W.R. is supported through the E. von
KU Leuven–University of Leuven, 1. Robberecht, W. & Philips, T. The changing scene of amyotrophic lateral Behring Chair for Neuromuscular and Neurodegenerative Disorders at KU
ALS2, alsin Rho guanine nucleotide exchange factor; AMPAR, AMPA receptor; heavy polypeptide; NEK1, NIMA-related kinase 1; NMDAR, NMDA receptor; NO, sclerosis. Nat. Rev. Neurosci. 14, 248–264 (2013).
Department of Neurosciences,
ANG, angiogenin; ATXN2, ataxin 2; BDNF, brain-derived neurotrophic factor; nitric oxide; OPTN, optineurin; PFN1, profilin 1; PRPH, peripherin; RBP, RNA-binding
Experimental Neurology and 2. Peters, O. M., Ghasemi, M. & Brown, R. H., Jr. Emerging mechanisms of Acknowledgements Leuven and by the European Research Council through ERC grant agreement
C9orf72, chromosome 9 open reading frame 72; CCNF, cyclin F; CHCHD10, coiled- protein; ROS, reactive oxygen species; SETX, senataxin; SIGMAR1, sigma non-opioid n° 340429.
Leuven Research Institute for molecular pathology in ALS. J. Clin. Invest. 125, 1767–1779 (2015). The authors are supported by grants from Opening the Future Fund (KU
coil-helix-coiled-coil-helix domain containing 10; CHMP2B, charged multivesicular intracellular receptor 1; SNP, single-nucleotide polymorphism; SOD1, superoxide 3. Haeusler, A. R., Donnelly, C. J. & Rothstein, J. D. The expanding biology of
body protein 2B; DAO, D-amino acid oxidase; DCTN1, dynactin subunit 1; EAAT2, dismutase 1; SPG11, spastic paraplegia 11; SQSTM1, sequestosome 1; TARDBP, TAR Neuroscience and Disease (LIND), Leuven), the Fund for Scientific Research Flanders (FWO-Flanders) and The poster content is peer reviewed, editorially independent and the sole
the C9orf72 nucleotide repeat expansion in neurodegenerative disease.
excitatory amino acid transporter 2; ELP3, elongator acetyltransferase complex sub- DNA-binding protein; TBK1, TANK-binding kinase 1; TDP43, TAR DNA-binding Leuven, Belgium. Nat. Rev. Neurosci. 17, 383–395 (2016). Flanders Innovation & Entrepreneurship (IWT grants Project MinE and responsibility of Macmillan Publishers Limited.
unit 3; EPHA4, ephrin type A receptor 4; ER, endoplasmic reticulum; FIG4, FIG4 protein 43; TGFβ, transforming growth factor-β; TH1, T helper 1 cell; TNF, tumour University Hospital Leuven, 4. Ling, S. C., Polymenidou, M. & Cleveland, D. W. Converging mechanisms in iPSCAF), the Interuniversity Attraction Poles (IUAP) program P7/16 of the Edited by Katherine Whalley; copyedited by Giulio Fiaschetti;
phospho­inositide 5-phosphatase; GDNF, glial cell line-derived neurotrophic factor; necrosis factor; Treg, regulatory T cell; TUBA4A, tubulin alpha 4A; UBQLN2, ubiquilin 2; Dept of Neurology, Leuven, Belgium. ALS and FTD: disrupted RNA and protein homeostasis. Neuron 79, 416–438 Belgian Federal Science Policy Office, the ALS Liga Belgium, the Association designed by Jennie Vallis.
GLE1, GLE1 RNA export mediator; HNRNPA1, heterogeneous nuclear ribonucleo- UNC13A, unc-13 homologue A; VAPB, VAMP-associated protein B and C; VCP, (2013). Belge contre les Maladies Neuro-Musculaires (ABMM), Hart voor ALS, Thierry © 2016 Macmillan Publishers Limited. All rights reserved.
VIB, Laboratory of Neurobiology, 5. Li, Y. R. et al. Stress granules as crucibles of ALS pathogenesis. J. Cell Biol. Latran Foundation, and the European Research Council under the European’s
protein A1; IGF2, insulin-like growth factor 2; IL, interleukin; MATR3, matrin 3; valosin-containing protein; VEGF, vascular endothelial growth factor.
Leuven, Belgium. 201, 361–372 (2013). Seventh Framework Programme (FP7/2007-2013) and under the Euro-MOTOR www.nature.com/nrn/posters/als
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