α-Synuclein strains target distinct brain regions and cell types

Abstract

The clinical and pathological differences between synucleinopathies such as Parkinson's disease and multiple system atrophy have been postulated to stem from unique strains of α-synuclein aggregates, akin to what occurs in prion diseases. Here, we demonstrate that inoculation of transgenic mice with different strains of recombinant or brain-derived α-synuclein aggregates produces clinically and pathologically distinct diseases. Strain-specific differences were observed in the signs of neurological illness, time to disease onset, morphology of cerebral α-synuclein deposits, and the conformational properties of the induced aggregates. Moreover, different strains targeted distinct cellular populations and cell types within the brain, recapitulating the selective targeting observed between human synucleinopathies. Strain-specific clinical, pathological, and biochemical differences were faithfully maintained upon serial passaging, implying that αsynuclein propagates via prion-like conformational templating. Thus, pathogenic α-synuclein exhibits key hallmarks of prion strains, providing evidence that disease heterogeneity among the synucleinopathies is caused by distinct α-synuclein strains.Parkinson's disease (PD) and related diseases, including dementia with Lewy bodies (DLB) and multiple system atrophy (MSA), are progressive neurodegenerative disorders. The brains of PD, DLB, and MSA patients contain intracellular inclusions composed of aggregated α-synuclein (α-syn). Thus, these diseases are commonly referred to as αsynucleinopathies, or simply synucleinopathies 1 . α-Syn is a 140-amino acid cytoplasmic protein that is found within presynaptic nerve terminals and is involved in the assembly of SNARE complexes 2 . In disease, α-syn polymerizes into insoluble β-sheet-rich protein aggregates that become phosphorylated at residue Ser129 and deposit within the central nervous system 3,4 . α-Syn is believed to play a central pathogenic role in the synucleinopathies since mutation of the gene encoding α-syn causes early-onset PD 5 .There is mounting evidence that α-syn becomes "prion-like" during disease, leading to a progressive cell-to-cell spreading of protein aggregates within the brain 6 . Prions are selfpropagating protein aggregates that cause neurodegenerative disorders such as Creutzfeldt-Jakob disease in humans and scrapie in sheep. Prion replication and spreading is thought to occur via a template-directed refolding mechanism, in which aggregated prion protein (PrP) catalyzes the conformational conversion of properly-folded PrP into additional copies of the misfolded form 7 . Similar to the experimental transmission of prion disease, injection of mice with pre-formed α-syn aggregates induces the aggregation and deposition of α-syn within the brain and, in some instances, accelerates the onset of neurological illness [8][9][10][11][12][13] . The prionlike behavior of α-syn aggregates provides a potential molecular explanation for the progressive nature of PD and related synucleinopathies.The synucleinopathies ar...

α-Synuclein aggregation intermediates form fibril polymorphs with distinct prion-like properties

“…Previously, various experimental conditions have been used to develop α-Syn fibrils polymorphs in vitro towards establishing their structure-pathogenic relationship [14][15][16][17] . These polymorphs often result in distinct clinical and pathological phenotypes in the animal models 18,19 .…”

“…Previously, various experimental conditions have been used to develop α-Syn fibrils polymorphs in vitro towards establishing their structure-pathogenic relationship [14][15][16][17] . These polymorphs often result in distinct clinical and pathological phenotypes in the animal models 18,19 .Since α-Syn amyloid formation involves a heterogeneous population of intermediate species [20][21][22] , we hypothesized that these intermediates species are capable of forming α-Syn polymorphs with distinct prion-like properties. Based on α-Syn aggregation intermediates, we developed two fibrillar polymorphs, PMF and HMF, with distinct fibril packing, structure and prion-like properties.…”

How would defining Parkinson’s as a prion disease impact the search of a cure?

“…Similar to prions, α-synuclein aggregates may present in different conformers (i.e. strains) [13,14] with relevant pathological and clinical implications [15]. The prion hypothesis for α-synuclein also accounts for Braak observations, which suggest that α-synuclein accumulation could begin either in the olfactory bulb or in the gastrointestinal tract and subsequently spread to the ventral midbrain, where it selectively affects dopamine neurons of the substantia nigra pars compacta (SNpc).…”

Targeting α-Synuclein for PD Therapeutics: A Pursuit on All Fronts

“…Recently, studies have aimed at identifying the different α-syn strains between synucleinopathies that could explain their divergent pathologies and clinical manifestations. It has been shown by several teams that there appears to be a specific aggregated form of α-syn that induces PD pathology [13][14][15].α-syn aggregation can be considered as a stochastic event, which would increase with age and/or cell stress conditions, forming initial seed nuclei that would escape cellular clearance due to perturbed proteostasis. Increased α-syn expression and point mutations have been extensively shown to promote aggregation [16].…”

“…Recently, studies have aimed at identifying the different α-syn strains between synucleinopathies that could explain their divergent pathologies and clinical manifestations. It has been shown by several teams that there appears to be a specific aggregated form of α-syn that induces PD pathology [13][14][15].…”