scholarly journals Autophagy Is a Common Degradation Pathway for Bunina Bodies and TDP-43 Inclusions in Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 78 (10) ◽  
pp. 910-921 ◽  
Author(s):  
Fumiaki Mori ◽  
Yasuo Miki ◽  
Tomoya Kon ◽  
Kunikazu Tanji ◽  
Koichi Wakabayashi
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Cathepsin B ◽  
Cathepsin D ◽  
Early Stage ◽  
Degradation Pathway ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Bunina Bodies ◽  
Related Proteins ◽  
Lateral Sclerosis

Abstract Bunina bodies (BBs) coexisting with TDP-43-immunoreactive (TDP-43-IR) skein-like inclusions (SIs) and round inclusions (RIs) in lower motor neurons are a frequent feature of sporadic amyotrophic lateral sclerosis (sALS). Since previous studies have shown that BBs and TDP-43-IR inclusions are often detected in association with autophagy-related structures (autophagosomes and autolysosomes), we examined the anterior horn cells (AHCs) of the spinal cord from 15 patients with sALS and 6 control subjects, using antibodies against autophagy-related proteins (LC3, cathepsin B, and cathepsin D). Among AHCs with SIs, 43.9% contained BBs, whereas 51.7% of AHCs with RIs did so. The cytoplasm of AHCs showed diffuse immunoreactivity for LC3, cathepsin B and cathepsin D in both sALS and controls. Ultrastructurally, SIs and mature BBs contained autophagosomes and autolysosomes. Mature BBs were localized in the vicinity of SIs. RIs also contained autophagosomes, autolysosomes, and early-stage BBs. These findings suggest that autophagy is a common degradation pathway for BBs and TDP-43-IR inclusions, which may explain their frequent coexistence.

scholarly journals Nuclear Phospho-SOD1 Protects DNA from Oxidative Stress Damage in Amyotrophic Lateral Sclerosis

2019 ◽  
Vol 8 (5) ◽  
pp. 729 ◽  
Author(s):  
Matteo Bordoni ◽  
Orietta Pansarasa ◽  
Michela Dell’Orco ◽  
Valeria Crippa ◽  
Stella Gagliardi ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Amyotrophic Lateral Sclerosis ◽  
Oxidative Damage ◽  
Motor Neurons ◽  
Mononuclear Cells ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Peripheral Blood Mononuclear ◽  
High Level ◽  
Lateral Sclerosis

We already demonstrated that in peripheral blood mononuclear cells (PBMCs) of sporadic amyotrophic lateral sclerosis (sALS) patients, superoxide dismutase 1 (SOD1) was present in an aggregated form in the cytoplasmic compartment. Here, we investigated the possible effect of soluble SOD1 decrease and its consequent aggregation. We found an increase in DNA damage in patients PBMCs characterized by a high level of aggregated SOD1, while we found no DNA damage in PBMCs with normal soluble SOD1. We found an activation of ataxia-telangiectasia-mutated (ATM)/Chk2 and ATM and Rad3-related (ATR)/Chk1 DNA damage response pathways, which lead to phosphorylation of SOD1. Moreover, data showed that phosphorylation allows SOD1 to shift from the cytoplasm to the nucleus, protecting DNA from oxidative damage. Such pathway was finally confirmed in our cellular model. Our data lead us to suppose that in a sub-group of patients this physiologic pathway is non-functional, leading to an accumulation of DNA damage that causes the death of particularly susceptible cells, like motor neurons. In conclusion, during oxidative stress SOD1 is phosphorylated by Chk2 leading to its translocation in the nuclear compartment, in which SOD1 protects DNA from oxidative damage. This pathway, inefficient in sALS patients, could represent an innovative therapeutic target.

Sympathetic Hyperactivity and Sympathovagal Imbalance in Amyotrophic Lateral Sclerosis

2012 ◽  
Vol 8 (1) ◽  
pp. 46 ◽  
Author(s):  
Toshio Shimizu ◽  
Keyword(s):  
Heart Rate ◽  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Neurodegenerative Disorder ◽  
Early Stage ◽  
Hypertensive Crisis ◽  
Individual Treatment ◽  
Sympathetic Hyperactivity ◽  
Sympathovagal Imbalance ◽  
Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder with progressive loss of upper and lower motor neurons. Autonomic nervous abnormalities, including sympathetic hyperactivity and sympathovagal imbalance, have been found in both early and advanced stages of ALS. In early stage, the dysfunction may be subclinical. Occasionally, elevated blood pressure or heart rate and increased sweating may be observed. In advanced stage when ventilators are required, the sympathetic hyperactivity may lead to hypertensive crisis without counter-regulation of heart rate, followed by the consecutive circulatory collapse, known as the ‘autonomic storm’. The symptoms of ‘autonomic storm’ are similar to that of ‘baroreflex failure’, and ‘autonomic storm’ indicates poor prognosis and may result in sudden death. Careful evaluation and individual treatment are strongly suggested, although appropriate therapeutic approaches have not been established. Causative central nervous lesions remain to be elucidated, although the limbic system may be involved. The autonomic dysfunction further supports the concept that ALS is a multisystem-degenerative disease.

scholarly journals Does Sporadic Amyotrophic Lateral Sclerosis Spread via Axonal Connectivities?

2017 ◽  
Vol 01 (03) ◽  
pp. E136-E141 ◽  
Author(s):  
H. Braak ◽  
M. Neumann ◽  
A. Ludolph ◽  
K. Del Tredici
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Motor Neurons ◽  
Pyramidal Cells ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Projection Neurons ◽  
Cortical Projection ◽  
Cytoplasmic Inclusions ◽  
Synaptic Contacts ◽  
Betz Cells ◽  
Lateral Sclerosis

AbstractThe pathological process underlying sporadic amyotrophic lateral sclerosis (sALS) that is associated with the formation of cytoplasmic inclusions of a nuclear protein (TDP-43) is confined to only a few types of long-axoned projection neurons. The giant Betz pyramidal cells of the primary motor neocortex as well as large α-motor neurons of the lower brainstem and spinal cord become involved early. In the human brain, these 2 neuronal types are to a large extent interconnected by monosynaptic axonal projections. The cell nuclei of affected neurons gradually forfeit their normal expression of the protein TDP-43. In α-motor neurons, this nuclear loss is followed by the formation of insoluble TDP-43-immunopositive inclusions in the cytoplasm, whereas in Betz cells the loss of nuclear expression remains for an unknown period of time unaccompanied by somatodendritic and/or axoplasmic aggregations. It is possible that in cortical pyramidal cells (Betz cells) the nuclear clearing initially leads to the formation of an abnormal but still soluble cytoplasmic TDP-43 which may enter the axoplasm and, following transmission via direct synaptic contacts, induces anew TDP-43 dysregulation and aggregation in recipient neurons. The trajectory of the spreading pattern that consecutively develops during the course of sALS is consistent with the dissemination from chiefly cortical projection neurons via axonal transport through direct synaptic contacts leading to the secondary induction of TDP-43-containing inclusions within recipient nerve cells in involved subcortical regions.

Elevated serum creatine kinase in the early stage of sporadic amyotrophic lateral sclerosis

2019 ◽  
Vol 266 (12) ◽  
pp. 2952-2961 ◽  
Author(s):  
Daisuke Ito ◽  
Atsushi Hashizume ◽  
Yasuhiro Hijikata ◽  
Shinichiro Yamada ◽  
Yohei Iguchi ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Creatine Kinase ◽  
Early Stage ◽  
Elevated Serum ◽  
Serum Creatine Kinase ◽  
Sporadic Amyotrophic Lateral Sclerosis ◽  
Lateral Sclerosis
Sign in / Sign up

Export Citation Format

Share Document