ALS: a disease of motor neurons and their nonneuronal neighbors.

https://www.cell.com/neuron/pdf/S0896-6273(12)00756-8.pdf

Synaptic Energy Use and Supply

Several recent breakthroughs have provided notable insights into the pathogenesis of amyotrophic lateral sclerosis (ALS), with some even shifting our thinking about this neurodegenerative disease and raising the question as to whether this disorder is a proteinopathy, a ribonucleopathy or both. In addition, these breakthroughs have revealed mechanistic links between ALS and frontotemporal dementia, as well as between ALS and other neurodegenerative diseases, such as the cerebellar atrophies, myotonic dystrophy and inclusion body myositis. Here, we summarize the new findings in ALS research, discuss what they have taught us about this disease and examine issues that are still outstanding.

/pdf/the-changing-scene-of-amyotrophic-lateral-sclerosis-1q1nhg9wa2.pdf

The changing scene of amyotrophic lateral sclerosis

A wide range of insults can trigger axon degeneration, and axons respond with diverse morphology, topology and speed. However, recent genetic, immunochemical, morphological and pharmacological investigations point to convergent degeneration mechanisms. The principal convergence points - poor axonal transport, mitochondrial dysfunction and an increase in intra-axonal calcium - have been identified by rescuing axons with the slow Wallerian degeneration gene (Wld(S)) and studies with blockers of sodium or calcium influx. By understanding how the pathways fit together, we can combine our knowledge of mechanisms, and potentially also treatment strategies, from different axonal disorders.

Axon degeneration mechanisms: commonality amid diversity

Neurodegenerative diseases can have long preclinical phases and insidious progression patterns, but the mechanisms of disease progression are poorly understood. Because quantitative accounts of neuronal circuitry affected by disease have been lacking, it has remained unclear whether disease progression reflects processes of stochastic loss or temporally defined selective vulnerabilities of distinct synapses or axons. Here we derive a quantitative topographic map of muscle innervation in the hindlimb. We show that in two mouse models of motoneuron disease (G93A SOD1 and G85R SOD1), axons of fast-fatiguable motoneurons are affected synchronously, long before symptoms appear. Fast-fatigue-resistant motoneuron axons are affected at symptom-onset, whereas axons of slow motoneurons are resistant. Axonal vulnerability leads to synaptic vesicle stalling and accumulation of BC12a1-a, an anti-apoptotic protein. It is alleviated by ciliary neurotrophic factor and triggers proteasome-dependent pruning of peripheral axon branches. Thus, motoneuron disease involves predictable, selective vulnerability patterns by physiological subtypes of axons, episodes of abrupt pruning in the target region and compensation by resistant axons.

Selective vulnerability and pruning of phasic motoneuron axons in motoneuron disease alleviated by CNTF

http://www.dns.ed.ac.uk/rrrweb/NMJHDhons/FischerGlassALSexpNeurol04.pdf

Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man.

The WldS gene modestly prolongs survival in the SOD1G93A fALS mouse.

Cilia are small microtubule-based structures found on the surface of most mammalian cells, which have key sensory and sometimes motile functions. Primary ciliary dyskinesia (PCD) is a type of ciliopathy caused by defects in motile cilia. The genetic basis of PCD is only partially understood. Studying a cohort of 11 human patients with PCD, we find that de novo mutations in TUBB4B, a beta tubulin isotype, cause three distinct classes of ciliopathic disease. In vivo studies in mice show that Tubb4b plays a specific role in cilia, building centrioles and axonemes in multiciliated cells. Examining the effects of specific TUBB4B variants in cells and in mice, we further demonstrate that distinct TUBB4B mutations differentially affect microtubule dynamics and cilia formation in a dominant negative manner. Finally, structure-function studies reveal that different TUBB4B mutations disrupt distinct tubulin interfaces. Importantly, these molecular differences correlate with disease features. We show that tubulin heterodimer-impairing TUBB4B variants underlie non-syndromic PCD, whilst additional renal and sensorineural ciliopathic features in a syndromic PCD subtype arise from microtubule lumenal interface-impaired TUBB4B variants. These findings suggest that specific tubulin isotypes have distinct and non-redundant subcellular functions, and demonstrate that human tubulinopathies can be drivers of ciliopathic syndromes.

Philip Tennant

Papers

Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man.

The WldS gene modestly prolongs survival in the SOD1G93A fALS mouse.

TUBB4B variants specifically impact ciliary function, causing a ciliopathic spectrum