Identical Seeding Characteristics and Cryo-EM Filament Structures in FTLD-Synuclein and Typical Multiple System Atrophy

被引：0

作者：

Cullinane, Patrick W. ^{[1
,2
,3
]}

Yang, Yang ^{[4
,5
]}

Chelban, Viorica ^{[6
]}

Goh, Yee Yen ^{[6
]}

Ebanks, Kirsten ^{[1
,2
]}

Curless, Toby ^{[1
,2
]}

Wrigley, Sarah ^{[1
,2
]}

de Pablo-Fernandez, Eduardo ^{[1
,2
]}

Holton, Janice ^{[2
]}

Peak-Chew, Sew ^{[4
]}

Franco, Catarina ^{[4
]}

Woerman, Amanda L. ^{[7
]}

Houlden, Henry ^{[6
]}

Warner, Thomas T. ^{[1
,2
,3
]}

Scheres, Sjors H. W. ^{[4
]}

Goedert, Michel ^{[4
]}

Jaunmuktane, Zane ^{[1
,2
,8
]}

机构：

[1] UCL Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, London, England

[2] UCL Queen Sq Inst Neurol, Queen Sq Brain Bank Neurol Disorders, London, England

[3] UCL Queen Sq Inst Neurol, Queen Sq Movement Disorders Ctr, London, England

[4] Med Res Council Lab Mol Biol, Cambridge, England

[5] Van Andel Inst, Dept Struct Biol, Grand Rapids, MI USA

[6] UCL Queen Sq Inst Neurol, Dept Neuromuscular Dis, London, England

[7] Colorado State Univ, Prion Res Ctr, Dept Microbiol Immunol & Pathol, Ft Collins, CO USA

[8] Univ Coll London NHS Fdn Trust, Natl Hosp Neurol & Neurosurg, Div Neuropathol, London, England

来源：

NEUROPATHOLOGY AND APPLIED NEUROBIOLOGY | 2025年 / 51卷 / 02期

基金：

英国医学研究理事会;

关键词：

cell-based seeding; cryo-EM; frontotemporal lobar degeneration; multiple system atrophy; alpha-synuclein; HEXANUCLEOTIDE REPEAT EXPANSIONS; ALPHA-SYNUCLEIN; NEURONAL INCLUSIONS; DEGENERATION; REFINEMENT; FRAMEWORK; DEMENTIA; MUTATION; PATIENT;

D O I：

10.1111/nan.70013

中图分类号：

R74 [神经病学与精神病学];

学科分类号：

摘要：

Aims: The aim of this study is to identify the prevalence of frontotemporal dementia (FTD)/corticobasal syndrome (CBS) in a large cohort of pathologically confirmed cases of multiple system atrophy (MSA) and to determine the alpha-synuclein seeding characteristics and electron cryo-microscopy (cryo-EM) filament structure in frontotemporal lobar degeneration with MSA-type alpha-synuclein pathology (FTLD-synuclein). Methods: The archives of the Queen Square Brain Bank (1989-2023) were searched for histologically confirmed MSA cases, and those with a clinical diagnosis of FTD/CBS were reviewed for pathological features of FTLD-synuclein. Phosphotungstic acid (PTA)-precipitated brain homogenates from FTLD-synuclein, dementia with Lewy bodies (DLB) and G51D SNCA synucleinopathy cases were used to seed aggregation in alpha-syn140*A53T-YFP HEK293T cells. The structure of alpha-synuclein filaments from an FTLD-synuclein case was determined by cryo-EM. Results: We identified 283 cases of MSA. Four cases had a clinical diagnosis of CBS, one of which met pathological criteria for FTLD-synuclein. Genetic studies in this case were negative for SNCA variants, and PTA-precipitated brain homogenates seeded abundant cytoplasmic alpha-synuclein inclusions that were morphologically indistinguishable from those of typical MSA but distinct from those of G51D SNCA and DLB. MSA Type II alpha-synuclein filaments were identified by cryo-EM. Conclusions: FTD/CBS is rarely associated with MSA pathology. The cell seeding characteristics and cryo-EM findings support the classification of FTLD-synuclein as a subtype of MSA, differentiating it from genetic synucleinopathies, such as those with SNCA variants G51D and A53E, which have neuropathological features overlapping with MSA and Lewy body diseases. These cases expand the clinicopathological spectrum of MSA and FTLD and have implications for our understanding of selective neuronal vulnerability in MSA and the interpretation of alpha-synuclein biomarker studies.

引用

页数：10

共 1 条

[1] Cryo-EM structure of a novel α-synuclein filament subtype from multiple system atrophy
Yan, Nicholas L.
Candido, Francisco
Tse, Eric
Melo, Arthur A.
Prusiner, Stanley B.
Mordes, Daniel A.
Southworth, Daniel R.
Paras, Nick A.
Merz, Gregory E.
FEBS LETTERS, 2025, 599 (01) : 33 - 40

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