Focality, stochasticity and neuroanatomic propagation in ALS pathogenesis

Ravits, John

doi:10.1016/j.expneurol.2014.07.021

Cited by 89 publications

(72 citation statements)

References 82 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…132, 133,134. In this issue, a detailed description can be found in the chapter titled “Primary Lateral Sclerosis.” By some estimates, PLS is approximately 0.5% as prevalent as ALS.…”

Section: Als Variantsmentioning

confidence: 99%

Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants

et al. 2015

Self Cite

View full text Add to dashboard Cite

Summary Amyotrophic lateral sclerosis (ALS) is a clinical syndrome named for its neuropathological hallmark: degeneration of motor neurons in the spinal anterior horn and motor cortex and loss of axons in the lateral columns of the spinal cord. The signature neuropathological molecular signature common to almost all sporadic ALS and most familial ALS is TDP-43 immunoreactive neuronal cytoplasmic inclusions. The neuropathological and molecular neuropathological features of ALS variants primarly lateral sclerosis and progressive muscular atrophy are less certain, but also appear to share the primary features of ALS. A number of genetic causes including mutations in SOD1, FUS, and C9orf72 comprise a disease spectrum and all demonstrate distinctive molecular and neuropathological signatures. Neuropathology will continue to play to a key role in solving the puzzle of ALS pathogenesis.

show abstract

“…132, 133,134. In this issue, a detailed description can be found in the chapter titled “Primary Lateral Sclerosis.” By some estimates, PLS is approximately 0.5% as prevalent as ALS.…”

Section: Als Variantsmentioning

confidence: 99%

Neuropathology of Amyotrophic Lateral Sclerosis and Its Variants

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…In ALS, this is often well recognised by a clear focal onset of clinical features which then spreads to neighbouring sites indicating disease propagation. (Ravits, 2014, Ravits et al, 2007a, Ravits and La Spada, 2009). Indeed, pathological examination corroborates clinical symptom spread, with a site of severe degeneration and cell loss from a focal onset in the neuraxis that diminishes further from the onset site (Ravits et al, 2007a, Ravits et al, 2007b).…”

Section: Introductionmentioning

confidence: 99%

In vitro prion-like behaviour of TDP-43 in ALS

Smethurst

Newcombe²,

Troakes

et al. 2016

Neurobiology of Disease

115

102

View full text Add to dashboard Cite

Amyotrophic lateral sclerosis (ALS) is the most common form of motor neuron disease (MND), and > 95% of familial and sporadic cases involve the deposition of insoluble aggregated, phosphorylated and cleaved TDP-43 protein. Accumulating clinical and biological evidence now indicates that ALS bears a number of similarities to the prion diseases, with TDP-43 acting as a misfolded ‘prion-like’ protein demonstrating similar underlying pathobiology. Here we systematically address the hypothesis that ALS is a prion-like disorder. First we demonstrate that TDP-43 demonstrates seeded polymerisation in vitro directly from both ALS brain and spinal cord. We next show that the seeding of TDP-43 results in the formation of characteristic insoluble, aggregated, and phosphorylated TDP-43 pathology that directly recapitulates the morphological diversity of TDP-43 inclusions detected in ALS patient CNS tissue. We next demonstrate that this reaction can be serially propagated to produce increasing amounts of phosphorylated TDP-43 pathology, and that aggregates can spread from cell to cell in an analogous fashion to that seen in the prion diseases. Finally, we reproduced our findings in a murine motor neuron-like cell line (NSC-34), where the seeding of TDP-43 induces the formation of TDP-43 oligomers and reduced cell viability. These findings may guide therapeutic strategies in this rapidly progressive and invariably fatal disease.

show abstract

“…Among various pathogenic factors, oxidative stress, mitochondrial dysfunction, apoptosis, glutamate excitotoxicity and proteasomal dysfunction are considered. However, the real cause of the disease, its natural history, classification, mechanism of progression and potential therapeutic targets are still under debate [13,[29][30][31]35,36,41].…”

Section: Discussionmentioning

confidence: 99%