α-synuclein inclusions are abundant in non-neuronal cells in the anterior olfactory nucleus of the Parkinson’s disease olfactory bulb

Stevenson, Taylor J.; Murray, Helen C.; Turner, Clinton; Faull, Richard L. M.; Dieriks, Birger; Curtis, Maurice A.

doi:10.1038/s41598-020-63412-x

Cited by 42 publications

(41 citation statements)

References 54 publications

(84 reference statements)

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“…An abundance of microglial αS inclusions described here has not been reported in humans [1], albeit very recently, microglia αS inclusions in the human olfactory bulb of PD patients have been described [49]. Furthermore, seeding-prone αS species were detected in human microglial exosomes isolated from CSF of sporadic PD and MSA patients [50] and microglia are involved in the spreading of αS lesions [51,52].…”

Section: Discussionmentioning

confidence: 48%

Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions

Tanriöver

Bacioglu

Schweighauser

et al. 2020

acta neuropathol commun

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Alpha-synucleinopathies are a group of progressive neurodegenerative disorders, characterized by intracellular deposits of aggregated α-synuclein (αS). The clinical heterogeneity of these diseases is thought to be attributed to conformers (or strains) of αS but the contribution of inclusions in various cell types is unclear. The aim of the present work was to study αS conformers among different transgenic (TG) mouse models of α-synucleinopathies. To this end, four different TG mouse models were studied (Prnp-h[A53T]αS; Thy1-h[A53T]αS; Thy1-h[A30P]αS; Thy1-mαS) that overexpress human or murine αS and differed in their age-of-symptom onset and subsequent disease progression. Postmortem analysis of end-stage brains revealed robust neuronal αS pathology as evidenced by accumulation of αS serine 129 (p-αS) phosphorylation in the brainstem of all four TG mouse lines. Overall appearance of the pathology was similar and only modest differences were observed among additionally affected brain regions. To study αS conformers in these mice, we used pentameric formyl thiophene acetic acid (pFTAA), a fluorescent dye with amyloid conformation-dependent spectral properties. Unexpectedly, besides the neuronal αS pathology, we also found abundant pFTAA-positive inclusions in microglia of all four TG mouse lines. These microglial inclusions were also positive for Thioflavin S and showed immunoreactivity with antibodies recognizing the N-terminus of αS, but were largely p-αS-negative. In all four lines, spectral pFTAA analysis revealed conformational differences between microglia and neuronal inclusions but not among the different mouse models. Concomitant with neuronal lesions, microglial inclusions were already present at presymptomatic stages and could also be induced by seeded αS aggregation. Although nature and significance of microglial inclusions for human αsynucleinopathies remain to be clarified, the previously overlooked abundance of microglial inclusions in TG mouse

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Section: Discussionmentioning

confidence: 48%

Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions

Tanriöver

Bacioglu

Schweighauser

et al. 2020

acta neuropathol commun

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“…OFB51 contained sparse distributed β-amyloid plaques and tau staining throughout the bulb. The levels observed within these normal cases are far below those observed in PD and AD bulbs, respectively (Kovács et al, 2001;Braak et al, 2003;Stevenson et al, 2020). No α-synuclein phospho ser129 or phospho-TDP-43 aggregates were found in the HD OFBs.…”

Section: Co-occurrence Of Tau Pathology Present In Hd Olfactory Bulbsmentioning

confidence: 65%

“…This suggests that the AON is a region susceptible to aggregate formation in HD and potentially plays a role in the olfactory deficits. This is a common feature observed across a range of neurodegenerative diseases but it remains unclear why aggregate pathology is highly concentrated within the AON, whether the disease is sporadic (most AD and PD cases) or purely genetic (HD) (Kovács et al, 2001;Braak et al, 2003;Stevenson et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

“…The AON regions were determined based on a combination of staining patterns. Namely, PGP9.5 staining, which labels the AON compartment and Hoechst staining that has less signal abundance in the AON due to the presence of large diffusely stained neuronal nuclei (Gardner et al, 2017;Stevenson et al, 2020). Following the segmentation, a precise measurement of the AON area was made.…”

Section: Quantificationmentioning

confidence: 99%

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Huntingtin Aggregates in the Olfactory Bulb in Huntington’s Disease

Highet

Dieriks

Murray

et al. 2020

Front. Aging Neurosci.

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Olfactory deficits are an early and prevalent non-motor symptom of Huntington's disease (HD). In other neurodegenerative diseases where olfactory deficits occur, such as Alzheimer's disease and Parkinson's disease, pathological protein aggregates (tau, β-amyloid, α-synuclein) accumulate in the anterior olfactory nucleus (AON) of the olfactory bulb (OFB). Therefore, in this study we determined whether aggregates are also present in HD OFBs; 13 HD and five normal human OFBs were stained for mutant huntingtin (mHtt), tau, β-amyloid, TDP-43, and α-synuclein. Our results show that mHtt aggregates detected with 1F8 antibody are present within all HD OFBs, and mHtt aggregate load in the OFB does not correlate with Vonsattel grading scores. The majority of the aggregates were located in the AON and in similar abundance in each anatomical segment of the AON. No mHtt aggregates were found in controls; 31% of HD cases also contained tau neurofibrillary tangles within the AON. This work demonstrates HD pathology in the OFB and indicates that disease-specific protein aggregation in the AON is a common feature of neurodegenerative diseases that show olfactory deficits.

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“…However, α-syn was scarce in olfactory cortices and it rarely co-localized with tyrosine hydroxylase 12 . It has recently been published that the α-syn are also localized in non-neuronal cells as glial and astroglial cells in the anterior olfactory nucleus 14 . Potential sexual dimorphic differences have only been occasionally addressed in the human OB 15 , showing that the number of neurons in females was 49.3% higher than males.…”

Section: Introductionmentioning

confidence: 99%

Astrogliosis and sexually dimorphic neurodegeneration and microgliosis in the olfactory bulb in Parkinson’s disease

Flores‐Cuadrado

Saiz-Sánchez

Mohedano-Moriano

et al. 2021

npj Parkinsons Dis.

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Hyposmia is prodromal, and male sex is a risk marker for an enhanced likelihood ratio of Parkinson’s disease. The literature regarding olfactory bulb volume reduction is controversial, although the olfactory bulb has been largely reported as an early and preferential site for α-synucleinopathy. These pathological deposits have been correlated with neural loss in Nissl-stained material. However, microgliosis has rarely been studied, and astrogliosis has been virtually neglected. In the present report, α-synucleinopathy (α-synuclein), neurodegeneration (Neu-N), astrogliosis (GFAP), and microgliosis (Iba-1) were quantified, using specific markers and stereological methods. Disease, sex, age, disease duration, and post-mortem interval were considered variables for statistical analysis. No volumetric changes have been identified regarding disease or sex. α-Synucleinopathy was present throughout the OB, mainly concentrated on anterior olfactory nucleus. Neurodegeneration (reduction in Neu-N-positive cells) was statistically significant in the diseased group. Astrogliosis (increased GFAP labeling) and microgliosis (increased Iba-1 labeling) were significantly enhanced in the Parkinson’s disease group. When analyzed per sex, neurodegeneration and microgliosis differences are only present in men. These data constitute the demonstration of sex differences in neurodegeneration using specific neural markers, enhanced astrogliosis and increased microgliosis, also linked to male sex, in the human olfactory bulb in Parkinson’s disease.

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α-synuclein inclusions are abundant in non-neuronal cells in the anterior olfactory nucleus of the Parkinson’s disease olfactory bulb

Cited by 42 publications

References 54 publications

Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions

Prominent microglial inclusions in transgenic mouse models of α-synucleinopathy that are distinct from neuronal lesions

Huntingtin Aggregates in the Olfactory Bulb in Huntington’s Disease

Astrogliosis and sexually dimorphic neurodegeneration and microgliosis in the olfactory bulb in Parkinson’s disease

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