Pathological TDP-43 changes in Betz cells differ from those in bulbar and spinal α-motoneurons in sporadic amyotrophic 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.

Download Full-text

Faculty Opinions recommendation of Novel optineurin mutations in patients with familial and sporadic amyotrophic lateral sclerosis.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.12796962.14073060 ◽

2011 ◽

Author(s):

Guy Rouleau

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Lateral Sclerosis

Download Full-text

Glutathione S-transferase Omega 2 DD genotype is associated with an increased risk of sporadic amyotrophic lateral sclerosis in Chinese men

Journal of International Medical Research ◽

10.1177/03000605211033219 ◽

2021 ◽

Vol 49 (7) ◽

pp. 030006052110332

Author(s):

Zhiliang Fan ◽

Hong Jiang ◽

Xueqin Song ◽

Yansu Guo ◽

Xinying Tian

Keyword(s):

Amyotrophic Lateral Sclerosis ◽

Healthy Subjects ◽

Chinese Population ◽

Sporadic Amyotrophic Lateral Sclerosis ◽

Glutathione S Transferase ◽

Genotype Frequencies ◽

Sporadic Als ◽

Increased Risk ◽

Chi Squared ◽

Lateral Sclerosis

Objective To investigate whether GSTA1, GSTO2, and GSTZ1 are relevant to an increased risk of amyotrophic lateral sclerosis (ALS) in a Chinese population. Methods In this study, 143 sporadic ALS (sALS) patients (83 men, 60 women) and 210 age- and sex-matched healthy subjects were enrolled. Blood samples were collected by venipuncture. Genomic DNA was isolated by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) according to the manufacturer’s instructions. The potential associations between ALS and GSTA1, GSTO2, and GSTZ1 polymorphisms were estimated using chi-squared analysis and unconditional logistic regression. Results The D allele and genotype frequencies of GSTO2 were increased in sALS patients compared with healthy subjects, indicating that the GSTO2 DD genotype was associated with an increased risk of sALS (odds ratio [OR] = 3.294, 95% confidence interval [CI] = 1.039–10.448). However, a significant association between the DD genotype and the risk of sALS was evident in men only (OR = 7.167, 95% CI = 1.381–37.202). Conclusion This study revealed that the D allele and genotype frequencies of GSTO2 were increased in sALS patients. The GSTO2 DD genotype was associated with an increased risk of sALS in men in a Chinese population.

Download Full-text