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Updated: May 20, 2025

Sequential Extraction of Soluble and Insoluble Alpha-Synuclein from Parkinsonian Brains

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Published on: January 5, 2016

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

Patrick W Cullinane^1,2,3, Yang Yang^4,5, Viorica Chelban⁶

¹Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK.

Neuropathology and Applied Neurobiology

|March 26, 2025

Summary

Frontotemporal dementia (FTD)/corticobasal syndrome (CBS) is rarely linked to multiple system atrophy (MSA) pathology. However, FTD with MSA-type alpha-synuclein pathology (FTLD-synuclein) represents a distinct subtype of MSA.

Keywords:

cell‐based seeding cryo‐EM frontotemporal lobar degeneration multiple system atrophy α‐synuclein

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Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo

Generation of Alpha-Synuclein Preformed Fibrils from Monomers and Use In Vivo

Published on: June 2, 2019

Area of Science:

Neuroscience
Neuropathology
Genetics

Background:

Multiple system atrophy (MSA) is a progressive neurodegenerative disorder characterized by autonomic dysfunction, parkinsonism, and ataxia.
Frontotemporal dementia (FTD) and corticobasal syndrome (CBS) are clinical syndromes typically associated with tauopathies or TDP-43 proteinopathies.
The overlap between MSA and FTD/CBS, particularly concerning alpha-synuclein pathology, remains incompletely understood.

Purpose of the Study:

To determine the prevalence of FTD/CBS in pathologically confirmed MSA cases.
To characterize the alpha-synuclein seeding properties in frontotemporal lobar degeneration with MSA-type alpha-synuclein pathology (FTLD-synuclein).
To elucidate the ultrastructure of alpha-synuclein filaments in FTLD-synuclein using cryo-electron microscopy (cryo-EM).

Main Methods:

Retrospective analysis of 283 pathologically confirmed MSA cases from the Queen Square Brain Bank (1989-2023).
Clinical and pathological review of cases with FTD/CBS features for FTLD-synuclein.
Alpha-synuclein seeding assays using HEK293T cells with brain homogenates from FTLD-synuclein, dementia with Lewy bodies (DLB), and G51D SNCA synucleinopathy cases.
Cryo-electron microscopy (cryo-EM) to determine the structure of alpha-synuclein filaments from an FTLD-synuclein case.

Main Results:

Only one out of 283 MSA cases met pathological criteria for FTLD-synuclein, despite four having a clinical diagnosis of CBS.
Alpha-synuclein inclusions in the FTLD-synuclein case were morphologically similar to typical MSA but distinct from G51D SNCA and DLB.
Cryo-EM identified MSA Type II alpha-synuclein filaments in the FTLD-synuclein case.

Conclusions:

FTD/CBS is an uncommon clinical presentation of MSA.
The seeding characteristics and cryo-EM structure support classifying FTLD-synuclein as a distinct subtype of MSA.
These findings differentiate FTLD-synuclein from genetic synucleinopathies and expand the clinicopathological spectrum of MSA and FTD.