Pale Neurites, Premature α‐Synuclein Aggregates with Centripetal Extension from Axon Collaterals

Kanazawa, Tohru; Adachi, Eijiro; Orimo, Satoshi; Nakamura, Ayako; Mizusawa, Hidehiro; Uchihara, Toshiki

doi:10.1111/j.1750-3639.2011.00509.x

Cited by 57 publications

(60 citation statements)

References 57 publications

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“…In addition, within the context of proteinopathies, in which the degradation and removal of abnormal proteins malfunction, both are linked with considerable certainty to the pathogenic process, because the breakdown of cellular mechanisms for degrading and clearing abnormal tau and a-synuclein make them ultimately deleterious to neuronal equilibrium (Chung et al 2001;Ciechanover 2005;Olanow and McNaught 2006;Rubinsztein 2006;Lim and Tan 2007;Upadhya and Hegde 2007a,b;Pan et al 2008;Lehman 2009;Kovacech et al 2010;Ebrahimi-Fakhari et al 2012;Kopeikina et al 2012;Tai et al 2012). There is also evidence that intra-axonal a-synuclein and intraneuronal tau aggregates are associated with axonopathy (Irizarry et al 1998;Saha et al 2004;Duda et al 2006;Stokin and Goldstein 2006;Orimo et al 2008;Kanazawa et al 2011;Lingor et al 2012;Lamberts et al 2015), cell membrane dysfunction (Tsigelny et al 2012), or cellular dysfunction (Dugger and Dickson 2010). Depending on study design, some experimental models display motor impairment, cognitive impairment, or deficits in neuronal excitability and/or cell loss (Giasson et al 2002;Sydow et al 2011;Volpicelli-Daley et al 2011;Luk et al 2012a;Sacino et al 2014;Brelstaff et al 2015;Ozcelik et al 2016).…”

Section: Discussionmentioning

confidence: 99%

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

Braak

Tredici

2016

Cold Spring Harb Perspect Biol

105

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Experimental data indicate that transneuronal propagation of abnormal protein aggregates in neurodegenerative proteinopathies, such as sporadic Alzheimer's disease (AD) and Parkinson's disease (PD), is capable of a self-propagating process that leads to a progression of neurodegeneration and accumulation of prion-like particles. The mechanisms by which misfolded tau and a-synuclein possibly spread from one involved nerve cell to the next in the neuronal chain to induce abnormal aggregation are still unknown. Based on findings from studies of human autopsy cases, we review potential pathways and mechanisms related to axonal and transneuronal dissemination of tau (sporadic AD) and a-synuclein (sporadic PD) aggregates between anatomically interconnected regions. S poradic Alzheimer's disease (AD) and Parkinson's disease (PD) are human neurodegenerative disorders that do not occur in other vertebrate species. Pathological hallmark lesions in AD and PD involve only a few types of nerve cells, mainly projection neurons. These lesions develop at predetermined predilection sites and progress according to predictable patterns (Braak and Del Tredici 2009, 2015). In AD, disease-related lesions remain confined to the central nervous system (CNS), whereas in PD they develop not only in the CNS but also in the enteric (ENS) and peripheral (PNS) nervous systems. Both diseases are caused by misfolding of specific proteins that are associated with aberrant aggregation. AD is primarily characterized by pathological forms of the intraneuronal protein tau (Goedert et al. 2006;Iqbal et al. 2009) and, thereafter gradually, by extracellular deposits of the b-amyloid protein (Ab) (Alafuzoff et al. 2009;Haass et al. 2012;Masters and Selkoe 2012). In mature nerve cells, the highest concentrations of the protein tau usually are found in the axon. Key lesions in sporadic PD consist of aggregated forms of a-synuclein, a protein located chiefly in axons and their presynaptic terminals (Eisenberg and Jucker 2012;Jucker and Walker 2013;Kaufman and Diamond 2013;Goedert et al. 2014). Notably, all brain regions and all types of nerve cells consecutively involved in AD or PD are anatomically interconnected over considerable distances, thereby indicating that physical contact among such interconnected nerve cells plays a key role in the pathogenesis of both illnesses (Pearson et al. 1985;Saper et al. 1987;Pearson and Powell 1989;Pearson 1996;Duyckaerts et al. 1997;Braak and Del Tredici 2011b). Ab is deposited extracellularly and thus is not known to transfer from one nerve cell to the next in the neuronal chain (Fiala 2007;Kaufman and Diamond 2013).Here, we focus on potential pathways and mechanisms related to the postulated transmission and transneuronal dissemination of tau and a-synuclein between involved neurons and as yet uninvolved neurons in anatomically connected regions (Brundin et al. 2008Clavaguera et al. 2009Clavaguera et al. , 2013aDesplats et al. 2009;Luk et al. 2009;Angot et al. 2010 Angot et al. , 2012Frost and Diamond 2010;Goedert...

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Section: Discussionmentioning

confidence: 99%

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

Braak

Tredici

2016

Cold Spring Harb Perspect Biol

105

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“…When used as immuolabeling reporters, Q-dots could be observed as fluorescent probes as well as electron-dense dots with a relatively homogeneous diameter. We took advantage of this dual visibility to compare LM findings of Pick bodies 25 or of Lewy neurites 26 with their exact EM counterparts. To facilitate EM recognition of the target, the fluorescent signal from the target lesion was reconstructed as 3D data.…”

Section: Electron Microscopymentioning

confidence: 99%

“…Our cell to cell comparison between fluorescent signal and silver impregnation is now being extended to 3D-oriented immunoelectron microscopy to examine the LM-identified targets with immuno EM so that direct comparison between LM and EM is possible. 25,26 Further improvement of this strategy is expected to show how RD3 and RD4 epitopes are ultrastructurally related to each other to feature their complementarity as seen in AD. Single staining for RD3 or RD4 disclosed RD4+ pretangles and RD3+ ghost tangles.…”

Section: Current Ambiguities and Future Perspectivementioning

confidence: 99%

Pretangles and neurofibrillary changes: Similarities and differences between AD and CBD based on molecular and morphological evolution

Uchihara

2014

Neuropathology

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Pretangles are cytoplasmic tau immunoreactivity in neurons without apparent formation of fibrillary structures. In Alzheimer disease, such tau deposition is considered to represent a premature state prior to fibril formation (AD-pretangles), later to form neurofibrillary tangles and finally ghost tangles. This morphological evolution from pretangles to ghost tangles is in parallel with their profile shift from four repeat (4R) tau-positive pretangles to three repeat (3R) tau-positive ghost tangles with both positive neurofibrillary tangles in between. This complementary shift of tau profile from 4R to 3R suggests that these tau epitopes are represented interchangeably along tangle evolution. Similar tau immunoreactivity without fibril formation is also observed in corticobasal degeneration (CBDpretangles). CBD-pretangles and AD-pretangles share: (i) selective 4R tau immunoreactivity without involvement of 3R tau; and (ii) argyrophilia with Gallyas silver impregnation. However, CBD-pretangles neither evolve into ghost tangles nor exhibit 3R tau immunoreactivity even at the advanced stage. Because electron microscopic studies on these pretangles are quite limited, it remains to be clarified whether such differences in later evolution are related to their primary ultrastructures, potentially distinct between AD and CBD. As double staining for 3R and 4R tau clarified complementary shift from 4R to 3R tau along evolution from pretangles to ghost tangles, double immunoelectron microscopy, if possible, may clarify similar profile shifts in relation to each tau fibril at the ultrastructural dimension. This will provide a unique viewpoint on how molecular (epitope) representations are related to pathogenesis of fibrillary components.

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“…The formation of axonal AS deposits and "pale bodies" [637] preceds the development of LBs in affected neurons. Loosely packed AS filaments as earliest or premature "pale neurites" are initiated at axon collaterals and extend centripetally into proximal segments [638]. (Table 2).…”

Section: Lbs In Transplanted Daergic Neurons Has Beenmentioning

confidence: 99%

The role of α-synuclein in neurodegeneration — An update

Jellinger¹

2012

Translational Neuroscience

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Genetic, neuropathological and biochemical evidence implicates α-synuclein, a 140 amino acid presynaptic neuronal protein, in the pathogenesis of Parkinson's disease and other neurodegenerative disorders. The aggregated protein inclusions mainly containing aberrant α-synuclein are widely accepted as morphological hallmarks of α-synucleinopathies, but their composition and location vary between disorders along with neuronal networks affected. α-Synuclein exists physiologically in both soluble and membran-bound states, in unstructured and α-helical conformations, respectively, while posttranslational modifications due to proteostatic deficits are involved in β-pleated aggregation resulting in formation of typical inclusions. The physiological function of α-synuclein and its role linked to neurodegeneration, however, are incompletely understood. Soluble oligomeric, not fully fibrillar α-synuclein is thought to be neurotoxic, main targets might be the synapse, axons and glia. The effects of aberrant α-synuclein include alterations of calcium homeostasis, mitochondrial dysfunction, oxidative and nitric injuries, cytoskeletal effects, and neuroinflammation. Proteasomal dysfunction might be a common mechanism in the pathogenesis of neuronal degeneration in α-synucleinopathies. However, how α-synuclein induces neurodegeneration remains elusive as its physiological function. Genome wide association studies demonstrated the important role for genetic variants of the SNCA gene encoding α-synuclein in the etiology of Parkinson's disease, possibly through effects on oxidation, mitochondria, autophagy, and lysosomal function. The neuropathology of synucleinopathies and the role of α-synuclein as a potential biomarker are briefly summarized. Although animal models provided new insights into the pathogenesis of Parkinson disease and multiple system atrophy, most of them do not adequately reproduce the cardinal features of these disorders. Emerging evidence, in addition to synergistic interactions of α-synuclein with various pathogenic proteins, suggests that prionlike induction and seeding of α-synuclein could lead to the spread of the pathology and disease progression. Intervention in the early aggregation pathway, aberrant cellular effects, or secretion of α-synuclein might be targets for neuroprotection and disease-modifying therapy.

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Pale Neurites, Premature α‐Synuclein Aggregates with Centripetal Extension from Axon Collaterals

Cited by 57 publications

References 57 publications

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

Potential Pathways of Abnormal Tau and α-Synuclein Dissemination in Sporadic Alzheimer's and Parkinson's Diseases

Pretangles and neurofibrillary changes: Similarities and differences between AD and CBD based on molecular and morphological evolution

The role of α-synuclein in neurodegeneration — An update

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