Ultrastructural and biochemical classification of pathogenic tau, α-synuclein and TDP-43

Abstract

Intracellular accumulation of abnormal proteins with conformational changes is the defining neuropathological feature of neurodegenerative diseases. The pathogenic proteins that accumulate in patients' brains adopt an amyloid-like fibrous structure and exhibit various ultrastructural features. The biochemical analysis of pathogenic proteins in sarkosyl-insoluble fractions extracted from patients’ brains also shows disease-specific features. Intriguingly, these ultrastructural and biochemical features are common within the same disease group. These differences among the pathogenic proteins extracted from patients’ brains have important implications for definitive diagnosis of the disease, and also suggest the existence of pathogenic protein strains that contribute to the heterogeneity of pathogenesis in neurodegenerative diseases. Recent experimental evidence has shown that prion-like propagation of these pathogenic proteins from host cells to recipient cells underlies the onset and progression of neurodegenerative diseases. The reproduction of the pathological features that characterize each disease in cellular and animal models of prion-like propagation also implies that the structural differences in the pathogenic proteins are inherited in a prion-like manner. In this review, we summarize the ultrastructural and biochemical features of pathogenic proteins extracted from the brains of patients with neurodegenerative diseases that accumulate abnormal forms of tau, α-synuclein, and TDP-43, and we discuss how these disease-specific properties are maintained in the brain, based on recent experimental insights.

A structural basis for prion strain diversity

“…1a). As with the previously reported RML pairs, it remains unclear self-propagating assemblies of tau, amyloid-β, α-synuclein and TDP-43 from human brain is now facilitating the detailed exploration of the role for strains in determining phenotype [16][17][18][19] .…”

Repetitive mild TBI causes pTau aggregation in nigra without altering preexisting fibril induced Parkinson’s-like pathology burden

“…Cross-seeding or corrupt templating has been shown to occur between αSyn and Tau as well as other proteins [ 67 , 68 ]. Increased pTau aggregation resulting from repetitive mild brain injuries may, in time, directly nucleate aggregation of αSyn serving as a corrupting template.…”

Hunting for the cause: Evidence for prion-like mechanisms in Huntington’s disease

“…mHTT isolated from the CSF of HD subjects or BACHD rats is seeding-competent ( Tan et al, 2015 ; Lee et al, 2020 ), suggesting that mHTT aggregates may propagate to peripheral tissues and mediate systemic HD pathologies ( Chuang and Demontis, 2021 ). Heterogeneity in the structure and toxicity of mHTT aggregates ( Shen et al, 2016 ; Ko et al, 2018 ; Mario Isas et al, 2021 ) implies the existence of mHTT strains that could be linked to variability in seeding ability or clinical HD phenotypes as seen for other amyloid aggregates ( Tarutani et al, 2022 ). Interestingly, lesions formed by other pathogenic proteins, such as tau and α-synuclein, are also present in HD patient brains ( Jellinger, 1998 ; Charles et al, 2000 ) and appear in fetal graft tissue ( Cisbani et al, 2017 ; Ornelas et al, 2020 ), suggesting common pathways driving protein aggregation in these diseases.…”